Adjuncts for surgical devices including agonists and antagonists

ABSTRACT

Adjuncts for surgical devices including agonists and antagonists are provided. In general, an implantable adjunct can have two or more medicants releasably disposed therein that are each releasable from the adjunct. At least one of the medicants can include an agonist configured to encourage a physiological response, and at least one of the medicants can include an antagonist configured to discourage the physiological response encouraged by the agonist. The physiological response can include an aspect of wound healing such that the aspect of wound healing may be both encouraged by and discouraged by the adjunct. The adjunct having one or more agonists and one or more antagonists releasably disposed therein can be configured to be applied to tissue by a surgical stapler in conjunction with staples.

FIELD

The present disclosure relates generally to adjuncts for surgicaldevices including agonists and antagonists.

BACKGROUND

Surgical staplers are used in surgical procedures to close openings intissue, blood vessels, ducts, shunts, or other objects or body partsinvolved in the particular procedure. The openings can be naturallyoccurring, such as passageways in blood vessels or an internal organlike the stomach, or they can be formed by the surgeon during a surgicalprocedure, such as by puncturing tissue or blood vessels to form abypass or an anastomosis, or by cutting tissue during a staplingprocedure.

Most staplers have a handle with an elongate shaft having a pair ofmovable opposed jaws formed on an end thereof for holding and formingstaples therebetween. The staples are typically contained in a staplecartridge, which can house multiple rows of staples and is oftendisposed in one of the two jaws for ejection of the staples to thesurgical site. In use, the jaws are positioned so that the object to bestapled is disposed between the jaws, and staples are ejected and formedwhen the jaws are closed and the device is actuated. Some staplersinclude a knife configured to travel between rows of staples in thestaple cartridge to longitudinally cut and/or open the stapled tissuebetween the stapled rows.

While surgical staplers have improved over the years, a number ofproblems still present themselves. One common problem is that leaks canoccur due to the staple forming holes when penetrating the tissue orother object in which it is disposed. Blood, air, gastrointestinalfluids, and other fluids can seep through the openings formed by thestaples, even after the staple is fully formed. The tissue being treatedcan also become inflamed due to the trauma that results from stapling.Still further, staples, as well as other objects and materials that canbe implanted in conjunction with procedures like stapling, generallylack some characteristics of the tissue in which they are implanted. Forexample, staples and other objects and materials can lack the naturalflexibility of the tissue in which they are implanted. A person skilledin the art will recognize that it is often desirable for tissue tomaintain as much of its natural characteristics as possible afterstaples are disposed therein.

In some instances, biologic materials have been used in conjunction withtissue stapling. However, the use of biologic materials presents anumber of additional problems. For example, it can be difficult tomaintain a location of the biologic material with respect to jaws of thestapler prior to and during staple ejection. It can also be difficult tokeep the biologic material at a desired location at the surgical siteafter stapling is completed. Further, it can be difficult to manufacturethe biologic material to a desired shape and thickness. Common plasticand molding manufacturing techniques are not generally conducive to themanufacture of thin biologic layers for use in conjunction with surgicalstaplers. The fragile nature of many biologic materials also makes themdifficult to use with surgical staplers because they lack structuralsupport.

Accordingly, there remains a need for improved devices and methods forstapling tissue, blood vessels, ducts, shunts, or other objects or bodyparts such that leaking and inflammation is minimized whilesubstantially maintaining the natural characteristics of the treatmentregion. There further remains a need for improved implantable materialsthat include biologics.

SUMMARY

In general, adjuncts for surgical devices including agonists andantagonists are provided.

In one aspect, a staple cartridge assembly for use with a surgicalstapler is provided that in one implementation includes a cartridgebody, a biocompatible adjunct material, a first medicant, and a secondmedicant. The cartridge body has a plurality of staple cavities. Eachstaple cavity has a surgical staple disposed therein. The biocompatibleadjunct material is releasably retained on the cartridge body and isconfigured to be delivered to tissue by deployment of the staples in thecartridge body. The first medicant is disposed within and is releasablefrom the adjunct material according to a predetermined release profile.The first medicant includes an agonist configured to encourage aphysiological response. The second medicant is disposed within and isreleasable from the adjunct material according to a predeterminedrelease profile. The second medicant includes an antagonist configuredto discourage the physiological response encouraged by the agonist.

The staple cartridge assembly can have any number of variations. Forexample, according to the predetermined release profile of the firstmedicant the agonist can be released from the adjunct material beforethe antagonist is released from the adjunct material according to thepredetermined release profile of the second medicant. For anotherexample, according to the predetermined release profile of the firstmedicant the agonist can be substantially fully released from theadjunct material before the antagonist begins release from the adjunctmaterial according to the predetermined release profile of the secondmedicant. For yet another example, the physiological response canincludes inflammation such that the agonist is configured to encouragetissue inflammation and the antagonist is configured to discouragetissue inflammation. For still another example, the adjunct material caninclude a plurality of fibers, the first medicant can be coated on afirst subset of the fibers, and the second medicant can be coated on asecond subset of the fibers.

For another example, a first plurality of coated capsules can bedisposed within the adjunct material, and a second plurality of coatedcapsules can be disposed within the adjunct material. Each of the firstplurality of coated capsules can have a coating surrounding the firstmedicant. Each of the second plurality of coated capsules can have acoating surrounding the second medicant. The coating of each of thefirst plurality of coated capsules can be configured to be bioabsorbedor dissolved prior to bioabsorption or dissolution of the coating ofeach of the second plurality of coated capsules such that the firstmedicant is configured to be released from the adjunct material prior tothe second medicant being released from the adjunct material.

For still another example, a plurality of capsules can be disposedwithin the adjunct material. Each of the capsules can include aplurality of bioabsorbable or dissolvable layers. The first medicant canbe included in a layer outer of a layer that includes the secondmedicant. The layer including the first medicant can be disposeddirectly adjacent to the layer including the second medicant, or a layerincluding a third medicant can be disposed between the layer includingthe first medicant and the layer including the second medicant.

In another aspect, an end effector for a surgical instrument is providedthat in one implementation includes a first jaw having a cartridge bodyremovably attached thereto, a second jaw having an anvil with aplurality of staple forming cavities formed on a tissue-facing surfacethereof, a biocompatible adjunct material, a first medicant, and asecond medicant. The cartridge body has on a tissue-facing surfacethereof a plurality of staple cavities configured to seat staplestherein. At least one of the first and second jaws is movable relativeto the other. The biocompatible adjunct material is releasably retainedon at least one of the tissue-facing surfaces of the cartridge body andthe anvil. The biocompatible adjunct material is configured to bedelivered to tissue by deployment of the staples in the cartridge body.The first medicant is disposed within and is releasable from the adjunctmaterial according to a predetermined release profile. The firstmedicant includes an agonist configured to encourage a physiologicalresponse. The second medicant is disposed within and is releasable fromthe adjunct material according to a predetermined release profile. Thesecond medicant includes an antagonist configured to discourage thephysiological response encouraged by the agonist.

The end effector can vary in any number of ways. For example, accordingto the predetermined release profile of the first medicant the agonistcan be released from the adjunct material before the antagonist isreleased from the adjunct material according to the predeterminedrelease profile of the second medicant. For another example, accordingto the predetermined release profile of the first medicant the agonistcan be substantially fully released from the adjunct material before theantagonist begins release from the adjunct material according to thepredetermined release profile of the second medicant. For yet anotherexample, the physiological response can include inflammation such thatthe agonist is configured to encourage tissue inflammation and theantagonist is configured to discourage tissue inflammation. For stillanother example, the adjunct material can include a plurality of fibers,the first medicant can be coated on a first subset of the fibers, andthe second medicant can be coated on a second subset of the fibers.

For another example, a first plurality of coated capsules can bedisposed within the adjunct material, and a second plurality of coatedcapsules can be disposed within the adjunct material. Each of the firstplurality of coated capsules can have a coating surrounding the firstmedicant. Each of the second plurality of coated capsules can have acoating surrounding the second medicant. The coating of each of thefirst plurality of coated capsules can be configured to be bioabsorbedor dissolved prior to bioabsorption or dissolution of the coating ofeach of the second plurality of coated capsules such that the firstmedicant is configured to be released from the adjunct material prior tothe second medicant being released from the adjunct material.

For yet another example, a plurality of capsules can be disposed withinthe adjunct material and can each include a plurality of bioabsorbableor dissolvable layers. The first medicant can be included in a layerouter of a layer that includes the second medicant. The layer includingthe first medicant can be disposed directly adjacent to the layerincluding the second medicant, or a layer including a third medicant canbe disposed between the layer including the first medicant and the layerincluding the second medicant.

BRIEF DESCRIPTION OF DRAWINGS

This invention will be more fully understood from the following detaileddescription taken in conjunction with the accompanying drawings, inwhich:

FIG. 1 is a perspective view of one embodiment of a surgical stapler;

FIG. 2 is an exploded view of a distal portion of the surgical staplerof FIG. 1;

FIG. 3 is a perspective view of a firing bar of the surgical stapler ofFIG. 1, the firing bar having an E-beam at a distal end thereof;

FIG. 4 is a perspective view of another embodiment of a surgicalstapler;

FIG. 5 is a perspective view of yet another embodiment of a surgicalstapler;

FIG. 6 is a graphical representation of an embodiment of an adjunctmaterial with different types of medicants encapsulated using differentrelease mechanisms before medicant release;

FIG. 7 is a graphical representation of the adjunct material of FIG. 6,showing release of a first medicant;

FIG. 8 is a graphical representation of the adjunct material of FIG. 6,showing release of a second medicant;

FIG. 9 is another graphical representation of an embodiment of anadjunct material with different types of medicants encapsulated usingdifferent release mechanisms before medicant release;

FIG. 10 is a graphical representation of the adjunct material of FIG. 9,showing release of the medicants as a result of absorption of a firstcoating;

FIG. 11 is a graphical representation of the adjunct material of FIG. 9,showing release of the medicants as a result of absorption of a secondcoating;

FIG. 12 is a graphical representation of an adjunct material includingtop and bottom layers of an absorbable polymer having differentdegradation rates;

FIG. 13 is a graphical representation of the adjunct material of FIG.12, showing a top layer partially degraded;

FIG. 14 is a graphical representation of the adjunct material of FIG.12, showing a bottom layer partially degraded after the top layer hasbeen degraded;

FIG. 15 is a graphical representation of an adjunct material configuredto release at least one medicant in response to at least oneenvironmental condition;

FIG. 16 is a graphical representation of the adjunct material of FIG.15, showing the at least one medicant partially released from theadjunct material in response to at least one environmental condition;

FIG. 17 is another graphical representation of the adjunct material ofFIG. 15, showing the at least one medicant substantially entirelyreleased from the adjunct material in response to at least oneenvironmental condition;

FIG. 18 is a graphical representation of an adjunct material configuredto release at least one medicant by changing its conformation;

FIG. 19 is a graphical representation of the adjunct material of FIG.18, showing the adjunct material with its conformation changes and theat least one medicant partially released;

FIG. 20 is a graphical representation of an adjunct material includingmultiple fibers associated with vessels having at least one medicantdisposed therein;

FIG. 21 is a graphical representation of the adjunct material of FIG.20, showing the at least one medicant released from the adjunct materialunder the effect of strain;

FIG. 22 is a graphical representation of an adjunct material configuredto release at least one medicant in response to strain applied to theadjunct material;

FIG. 23 is a graphical representation of the adjunct material of FIG.22, showing the at least one medicant being released in response tostrain applied to the adjunct material;

FIG. 24 is a graphical representation of a vessel having at least onemedicant encapsulated therein;

FIG. 25 is a graphical representation of the vessel of FIG. 24, showingthe at least one medicant being released in response to strain appliedto the vessel;

FIG. 26 is a graphical representation of an adjunct material configuredto release at least one medicant when the adjunct material changes itsconformation;

FIG. 27 is a graphical representation of the adjunct material of FIG.26, showing the at least one medicant being released in response achange in the conformation of the adjunct material;

FIG. 28 is another graphical representation of an adjunct materialconfigured to release at least one medicant when the adjunct materialchanges its conformation;

FIG. 29 is a graphical representation of the adjunct material of FIG.28, showing the at least one medicant being released in response achange in the conformation of the adjunct material;

FIG. 30 is a graphical representation of an adjunct material havingvessels configured to release at least one medicant encapsulated thereinin a non-homogeneous manner;

FIG. 31 is a graphical representation of a vessel configured to releasemultiple medicants encapsulated at different layers thereof in anon-homogeneous manner;

FIG. 32 is a graphical representation of an adjunct material havingdifferent portions configured to release at least one medicant in anon-homogeneous manner;

FIG. 33 is another graphical representation of an adjunct materialhaving different portions configured to release at least one medicant ina non-homogeneous manner;

FIG. 34 is a graphical representation of a side view of the adjunctmaterial of FIG. 33;

FIG. 35 is a graphical representation of a side view of an adjunctmaterial having different portions configured to release at least onemedicant in a non-homogeneous manner;

FIG. 36 is another graphical representation of a side view of an adjunctmaterial having different portions configured to release at least onemedicant in a non-homogeneous manner;

FIG. 37 is a graphical representation of an adjunct material havingdifferent concentric regions configured to release at least one medicantat different rates;

FIG. 38 is a graphical representation of an adjunct material havingdifferent radial regions configured to release at least one medicant atdifferent rates;

FIG. 39 is another graphical representation of an adjunct materialhaving different concentric regions configured to release at least onemedicant at different rates;

FIG. 40 is a graphical representation of an embodiment of wound healingover time with doses of medicants;

FIG. 41 is a graphical representation of a hemostatic stage in the woundhealing of FIG. 40;

FIG. 42 is a graphical representation of a portion of an inflammationstage in the wound healing of FIG. 40;

FIG. 43 is a graphical representation of another portion of theinflammation stage in the wound healing of FIG. 40;

FIG. 44 is a graphical representation of a proliferation stage in thewound healing of FIG. 40;

FIG. 45 is a graph showing implementations of cumulative doses ofmedicants in which the medicants include at least one agonist and atleast one antagonist;

FIG. 46 is a graph showing an implementation of doses of medicants inwhich the medicants include at least one agonist and at least oneantagonist;

FIG. 47 is a graph showing a portion of the graph of FIG. 46 andindicating a cumulative dose;

FIG. 48 is a graphical representation of an implementation of a layeredvessel including a medicant that includes an agonist and anothermedicant that includes an antagonist;

FIG. 49 is a perspective view of an implementation of a fiber having acoating therearound configured to facilitate release of an agonistand/or an antagonist;

FIG. 50 is a cross-sectional view of the fiber and coating of FIG. 49;

FIG. 51 is a perspective view of another implementation of a fiberhaving a coating therearound configured to facilitate release of anagonist and/or an antagonist;

FIG. 52 is a cross-sectional view of the fiber and coating of FIG. 51;and

FIG. 53 is a perspective view of a portion of an implementation of animplantable adjunct formed from a plurality of fibers woven together toform a sheet-like fiber woven mesh configured to facilitate release ofan agonist and an antagonist.

DETAILED DESCRIPTION

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the structure, function,manufacture, and use of the devices and methods disclosed herein. One ormore examples of these embodiments are illustrated in the accompanyingdrawings. Those skilled in the art will understand that the devices andmethods specifically described herein and illustrated in theaccompanying drawings are non-limiting exemplary embodiments and thatthe scope of the present invention is defined solely by the claims. Thefeatures illustrated or described in connection with one exemplaryembodiment may be combined with the features of other embodiments. Suchmodifications and variations are intended to be included within thescope of the present invention.

Further, in the present disclosure, like-named components of theembodiments generally have similar features, and thus within aparticular embodiment each feature of each like-named component is notnecessarily fully elaborated upon. Additionally, to the extent thatlinear or circular dimensions are used in the description of thedisclosed systems, devices, and methods, such dimensions are notintended to limit the types of shapes that can be used in conjunctionwith such systems, devices, and methods. A person skilled in the artwill recognize that an equivalent to such linear and circular dimensionscan easily be determined for any geometric shape. Sizes and shapes ofthe systems and devices, and the components thereof, can depend at leaston the anatomy of the subject in which the systems and devices will beused, the size and shape of components with which the systems anddevices will be used, and the methods and procedures in which thesystems and devices will be used.

It will be appreciated that the terms “proximal” and “distal” are usedherein with reference to a user, such as a clinician, gripping a handleof an instrument. Other spatial terms such as “front” and “back”similarly correspond respectively to distal and proximal. It will befurther appreciated that for convenience and clarity, spatial terms suchas “vertical” and “horizontal” are used herein with respect to thedrawings. However, surgical instruments are used in many orientationsand positions, and these spatial terms are not intended to be limitingand absolute.

Various exemplary devices and methods are provided for performingsurgical procedures. In some embodiments, the devices and methods areprovided for open surgical procedures, and in other embodiments, thedevices and methods are provided for laparoscopic, endoscopic, and otherminimally invasive surgical procedures. The devices may be fireddirectly by a human user or remotely under the direct control of a robotor similar manipulation tool. However, a person skilled in the art willappreciate that the various methods and devices disclosed herein can beused in numerous surgical procedures and applications. Those skilled inthe art will further appreciate that the various instruments disclosedherein can be inserted into a body in any way, such as through a naturalorifice, through an incision or puncture hole formed in tissue, orthrough an access device, such as a trocar cannula. For example, theworking portions or end effector portions of the instruments can beinserted directly into a patient's body or can be inserted through anaccess device that has a working channel through which the end effectorand elongated shaft of a surgical instrument can be advanced.

It can be desirable to use one or more biologic materials and/orsynthetic materials, collectively referred to herein as “adjuncts,” inconjunction with surgical instruments to help improve surgicalprocedures. While a variety of different surgical end effectors canbenefit from the use of adjuncts, in some exemplary embodiments the endeffector can be a surgical stapler. When used in conjunction with asurgical stapler, the adjunct(s) can be disposed between and/or on jawsof the stapler, incorporated into a staple cartridge disposed in thejaws, or otherwise placed in proximity to the staples. When staples aredeployed, the adjunct(s) can remain at the treatment site with thestaples, in turn providing a number of benefits. For example, theadjunct(s) may reinforce tissue at the treatment site, preventingtearing or ripping by the staples at the treatment site. Tissuereinforcement may be needed to keep the staples from tearing through thetissue if the tissue is diseased, is healing from another treatment suchas irradiation, medications such as chemotherapy, or other tissueproperty altering situation. In some instances, the adjunct(s) mayminimize tissue movement in and around the staple puncture sites thatcan occur from tissue deformation that occurs after stapling (e.g., lunginflation, gastrointestinal tract distension, etc.). It will berecognized by one skilled in the art that a staple puncture site mayserve as a stress concentration and that the size of the hole created bythe staple will grow when the tissue around it is placed under tension.Restricting the tissues movement around these puncture sites canminimize the size the holes may grow to under tension. In someinstances, the adjunct(s) can be configured to wick or absorb beneficialfluids, e.g., sealants, blood, glues, that further promote healing, andin some instances, the adjunct(s) can be configured to degrade to form agel, e.g., a sealant, that further promotes healing. In some instances,the adjunct(s) can be used to help seal holes formed by staples as theyare implanted into tissue, blood vessels, and various other objects orbody parts. The adjunct(s) may also affect tissue growth through thespacing, positioning and/or orientation of any fibers or strandsassociated with the adjunct(s).

The adjunct(s) can also have medicant(s) thereon and/or therein. Themedicant(s) can vary depending on the desired effect of the medicant(s)on the surrounding tissue. As a non-limiting example, medicant(s) can beprovided to influence hemostasis, inflammation, macrophages, and/orfibroblasts. Medicant(s) can be mixed or combined in any combination ora medicant can be provided alone, again depending on the desired effecton the tissue. The medicant(s) can be eluted from the adjunct(s) in avariety of different ways. As non-limiting examples, coatings on theadjunct(s) can be varied to be absorbed at different times, therebyreleasing the medicant(s) at different times; the adjunct(s) can bevaried to allow diffusion of the medicant(s) across the adjunct(s) atvarying rates; the adjunct(s) can vary in molecular weight and/orphysical characteristics to cause release of the medicant(s) atdifferent times; etc.

Surgical Stapling Instruments

A variety of surgical instruments can be used in conjunction with theadjunct(s) and/or medicant(s) disclosed herein. “Adjuncts” are alsoreferred to herein as “adjunct materials.” The surgical instruments caninclude surgical staplers. A variety of surgical staplers can be used,for example linear surgical staplers and circular staplers. In general,a linear stapler can be configured to create longitudinal staple linesand can include elongate jaws with a cartridge coupled theretocontaining longitudinal staple rows. The elongate jaws can include aknife or other cutting element capable of creating a cut between thestaple rows along tissue held within the jaws. In general, a circularstapler can be configured to create annular staple lines and can includecircular jaws with a cartridge containing annular staple rows. Thecircular jaws can include a knife or other cutting element capable ofcreating a cut inside of the rows of staples to define an openingthrough tissue held within the jaws. The staplers can be used in avariety of different surgical procedures on a variety of tissues in avariety of different surgical procedures, for example in thoracicsurgery or in gastric surgery.

FIG. 1 illustrates one example of a linear surgical stapler 10 suitablefor use with one or more adjunct(s) and/or medicant(s). The stapler 10generally includes a handle assembly 12, a shaft 14 extending distallyfrom a distal end 12 d of the handle assembly 12, and an end effector 30at a distal end 14 d of the shaft 14. The end effector 30 has opposedlower and upper jaws 32, 34, although other types of end effectors canbe used with the shaft 14, handle assembly 12, and components associatedwith the same. The lower jaw 32 has a staple channel 56 configured tosupport a staple cartridge 40, and the upper jaw 34 has an anvil surface33 that faces the lower jaw 32 and that is configured to operate as ananvil to help deploy staples of the staple cartridge 40 (the staples areobscured in FIG. 1 and FIG. 2). At least one of the opposed lower andupper jaws 32, 34 is moveable relative to the other lower and upper jaws32, 34 to clamp tissue and/or other objects disposed therebetween. Insome implementations, one of the opposed lower and upper jaws 32, 34 maybe fixed or otherwise immovable. In some implementations, both of theopposed lower and upper jaws 32, 34 may be movable. Components of afiring system can be configured to pass through at least a portion ofthe end effector 30 to eject the staples into the clamped tissue. Invarious implementations a knife blade 36 or other cutting element can beassociated with the firing system to cut tissue during the staplingprocedure.

Operation of the end effector 30 can begin with input from a user, e.g.,a clinician, a surgeon, etc., at the handle assembly 12. The handleassembly 12 can have many different configurations designed tomanipulate and operate the end effector 30 associated therewith. In theillustrated example, the handle assembly 12 has a pistol-grip typehousing 18 with a variety of mechanical and/or electrical componentsdisposed therein to operate various features of the instrument 10. Forexample, the handle assembly 12 can include a rotation knob 26 mountedadjacent a distal end 12 d thereof which can facilitate rotation of theshaft 14 and/or the end effector 30 with respect to the handle assembly12 about a longitudinal axis L of the shaft 14. The handle assembly 12can further include clamping components as part of a clamping systemactuated by a clamping trigger 22 and firing components as part of thefiring system that are actuated by a firing trigger 24. The clamping andfiring triggers 22, 24 can be biased to an open position with respect toa stationary handle 20, for instance by a torsion spring. Movement ofthe clamping trigger 22 toward the stationary handle 20 can actuate theclamping system, described below, which can cause the jaws 32, 34 tocollapse towards each other and to thereby clamp tissue therebetween.Movement of the firing trigger 24 can actuate the firing system,described below, which can cause the ejection of staples from the staplecartridge 40 disposed therein and/or the advancement the knife blade 36to sever tissue captured between the jaws 32, 34. A person skilled inthe art will recognize that various configurations of components for afiring system, mechanical, hydraulic, pneumatic, electromechanical,robotic, or otherwise, can be used to eject staples and/or cut tissue.

As shown in FIG. 2, the end effector 30 of the illustratedimplementation has the lower jaw 32 that serves as a cartridge assemblyor carrier and the opposed upper jaw 34 that serves as an anvil. Thestaple cartridge 40, having a plurality of staples therein, is supportedin a staple tray 37, which in turn is supported within a cartridgechannel of the lower jaw 32. The upper jaw 34 has a plurality of stapleforming pockets (not shown), each of which is positioned above acorresponding staple from the plurality of staples contained within thestaple cartridge 40. The upper jaw 34 can be connected to the lower jaw32 in a variety of ways, although in the illustrated implementation theupper jaw 34 has a proximal pivoting end 34 p that is pivotally receivedwithin a proximal end 56 p of the staple channel 56, just distal to itsengagement to the shaft 14. When the upper jaw 34 is pivoted downwardly,the upper jaw 34 moves the anvil surface 33 and the staple formingpockets formed thereon move toward the opposing staple cartridge 40.

Various clamping components can be used to effect opening and closing ofthe jaws 32, 34 to selectively clamp tissue therebetween. Asillustrated, the pivoting end 34 p of the upper jaw 34 includes aclosure feature 34 c distal to its pivotal attachment with the staplechannel 56. Thus, a closure tube 46, whose distal end includes ahorseshoe aperture 46 a that engages the closure feature 34 c,selectively imparts an opening motion to the upper jaw 34 duringproximal longitudinal motion and a closing motion to the upper jaw 34during distal longitudinal motion of the closure tube 46 in response tothe clamping trigger 22. As mentioned above, in various implementations,the opening and closure of the end effector 30 may be effected byrelative motion of the lower jaw 32 with respect to the upper jaw 34,relative motion of the upper jaw 34 with respect to the lower jaw 32, orby motion of both jaws 32, 34 with respect to one another.

The firing components of the illustrated implementation includes afiring bar 35, as shown in FIG. 3, having an E-beam 38 on a distal endthereof. The firing bar 35 is encompassed within the shaft 14, forexample in a longitudinal firing bar slot 14 s of the shaft 14, andguided by a firing motion from the handle 12. Actuation of the firingtrigger 24 can affect distal motion of the E-beam 38 through at least aportion of the end effector 30 to thereby cause the firing of staplescontained within the staple cartridge 40. As illustrated, guides 39projecting from a distal end of the E-Beam 38 can engage a wedge sled 47shown in FIG. 2, which in turn can push staple drivers 48 upwardlythrough staple cavities 41 formed in the staple cartridge 40. Upwardmovement of the staple drivers 48 applies an upward force on each of theplurality of staples within the cartridge 40 to thereby push the staplesupwardly against the anvil surface 33 of the upper jaw 34 and createformed staples.

In addition to causing the firing of staples, the E-beam 38 can beconfigured to facilitate closure of the jaws 32, 34, spacing of theupper jaw 34 from the staple cartridge 40, and/or severing of tissuecaptured between the jaws 32, 34. In particular, a pair of top pins anda pair of bottom pins can engage one or both of the upper and lower jaws32, 34 to compress the jaws 32, 34 toward one another as the firing bar35 advances through the end effector 30. Simultaneously, the knife 36extending between the top and bottom pins can be configured to severtissue captured between the jaws 32, 34.

In use, the surgical stapler 10 can be disposed in a cannula or port anddisposed at a surgical site. A tissue to be cut and stapled can beplaced between the jaws 32, 34 of the surgical stapler 10. Features ofthe stapler 10 can be maneuvered as desired by the user to achieve adesired location of the jaws 32,34 at the surgical site and the tissuewith respect to the jaws 32, 34. After appropriate positioning has beenachieved, the clamping trigger 22 can be pulled toward the stationaryhandle 20 to actuate the clamping system. The trigger 22 can causecomponents of the clamping system to operate such that the closure tube46 advances distally through at least a portion of the shaft 14 to causeat least one of the jaws 32, 34 to collapse towards the other to clampthe tissue disposed therebetween. Thereafter, the trigger 24 can bepulled toward the stationary handle 20 to cause components of the firingsystem to operate such that the firing bar 35 and/or the E-beam 38 areadvanced distally through at least a portion of the end effector 30 toeffect the firing of staples and optionally to sever the tissue capturedbetween the jaws 32, 34.

Another example of a surgical instrument in the form of a linearsurgical stapler 50 is illustrated in FIG. 4. The stapler 50 cangenerally be configured and used similar to the stapler 10 of FIG. 1.Similar to the surgical instrument 10 of FIG. 1, the surgical instrument50 includes a handle assembly 52 with a shaft 54 extending distallytherefrom and having an end effector 60 on a distal end thereof fortreating tissue. Upper and lower jaws 64, 62 of the end effector 60 canbe configured to capture tissue therebetween, staple the tissue byfiring of staples from a cartridge 66 disposed in the lower jaw 62,and/or to create an incision in the tissue. In this implementation, anattachment portion 67 on a proximal end of the shaft 54 can beconfigured to allow for removable attachment of the shaft 54 and the endeffector 60 to the handle assembly 52. In particular, mating features 68of the attachment portion 67 can mate to complementary mating features71 of the handle assembly 52. The mating features 68, 71 can beconfigured to couple together via, e.g., a snap fit coupling, a bayonettype coupling, etc., although any number of complementary matingfeatures and any type of coupling can be used to removably couple theshaft 54 to the handle assembly 52. Although the entire shaft 54 of theillustrated implementation is configured to be detachable from thehandle assembly 52, in some implementations, the attachment portion 67can be configured to allow for detachment of only a distal portion ofthe shaft 54. Detachable coupling of the shaft 54 and/or the endeffector 60 can allow for selective attachment of a desired end effector60 for a particular procedure, and/or for reuse of the handle assembly52 for multiple different procedures.

The handle assembly 52 can have one or more features thereon tomanipulate and operate the end effector 60. By way of non-limitingexample, a rotation knob 72 mounted on a distal end of the handleassembly 52 can facilitate rotation of the shaft 54 and/or the endeffector 60 with respect to the handle assembly 52. The handle assembly52 can include clamping components as part of a clamping system actuatedby a movable trigger 74 and firing components as part of a firing systemthat can also be actuated by the trigger 74. Thus, in someimplementations, movement of the trigger 74 toward a stationary handle70 through a first range of motion can actuate clamping components tocause the opposed jaws 62, 64 to approximate toward one another to aclosed position. In some implementations, only one of the opposed jaws62, 24 can move to the jaws 62, 64 to the closed position. Furthermovement of the trigger 74 toward the stationary handle 70 through asecond range of motion can actuate firing components to cause theejection of the staples from the staple cartridge 66 and/or theadvancement of a knife or other cutting element (not shown) to severtissue captured between the jaws 62, 64.

One example of a surgical instrument in the form of a circular surgicalstapler 80 is illustrated in FIG. 5. The stapler 80 can generally beconfigured and used similar to the linear staplers 10, 50 of FIG. 1 andFIG. 4, but with some features accommodating its functionality as acircular stapler. Similar to the surgical instruments 10, 50, thesurgical instrument 80 includes a handle assembly 82 with a shaft 84extending distally therefrom and having an end effector 90 on a distalend thereof for treating tissue. The end effector 90 can include acartridge assembly 92 and an anvil 94, each having a tissue-contactingsurface that is substantially circular in shape. The cartridge assembly92 and the anvil 94 can be coupled together via a shaft 98 extendingfrom the anvil 94 to the handle assembly 82 of the stapler 80, andmanipulating an actuator 85 on the handle assembly 82 can retract andadvance the shaft 98 to move the anvil 94 relative to the cartridgeassembly 92. The anvil 94 and cartridge assembly 92 can perform variousfunctions and can be configured to capture tissue therebetween, staplethe tissue by firing of staples from a cartridge 96 of the cartridgeassembly 92 and/or can create an incision in the tissue. In general, thecartridge assembly 92 can house a cartridge containing the staples andcan deploy staples against the anvil 94 to form a circular pattern ofstaples, e.g., staple around a circumference of a tubular body organ.

In one implementation, the shaft 98 can be formed of first and secondportions (not shown) configured to releasably couple together to allowthe anvil 94 to be detached from the cartridge assembly 92, which mayallow greater flexibility in positioning the anvil 94 and the cartridgeassembly 92 in a body of a patient. For example, the first portion ofthe shaft can be disposed within the cartridge assembly 92 and extenddistally outside of the cartridge assembly 92, terminating in a distalmating feature. The second portion of the shaft 84 can be disposedwithin the anvil 94 and extend proximally outside of the cartridgeassembly 92, terminating in a proximal mating feature. In use, theproximal and distal mating features can be coupled together to allow theanvil 94 and cartridge assembly 92 to move relative to one another.

The handle assembly 82 of the stapler 80 can have various actuatorsdisposed thereon that can control movement of the stapler. For example,the handle assembly 82 can have a rotation knob 86 disposed thereon tofacilitate positioning of the end effector 90 via rotation, and/or thetrigger 85 for actuation of the end effector 90. Movement of the trigger85 toward a stationary handle 87 through a first range of motion canactuate components of a clamping system to approximate the jaws, i.e.move the anvil 94 toward the cartridge assembly 92. Movement of thetrigger 85 toward the stationary handle 87 through a second range ofmotion can actuate components of a firing system to cause the staples todeploy from the staple cartridge assembly 92 and/or cause advancement ofa knife to sever tissue captured between the cartridge assembly 92 andthe anvil 94.

The illustrated examples of surgical stapling instruments 10, 50, and 80provide only a few examples of many different configurations, andassociated methods of use, that can be used in conjunction with thedisclosures provided herein. Although the illustrated examples are allconfigured for use in minimally invasive procedures, it will beappreciated that instruments configured for use in open surgicalprocedures, e.g., open linear staplers as described in U.S. Pat. No.8,317,070 entitled “Surgical Stapling Devices That Produce FormedStaples Having Different Lengths” and filed Feb. 28, 2007, can be usedin conjunction with the disclosures provided herein. Greater detail onthe illustrated examples, as well as additional examples of surgicalstaplers, components thereof, and their related methods of use, areprovided in U.S. Pat. Pub. No. 2013/0256377 entitled “Layer ComprisingDeployable Attachment Members” and filed Feb. 8, 2013, U.S. Pat. No.8,393,514 entitled “Selectively Orientable Implantable FastenerCartridge” and filed Sep. 30, 2010, U.S. Pat. No. 8,317,070 entitled“Surgical Stapling Devices That Produce Formed Staples Having DifferentLengths” and filed Feb. 28, 2007, U.S. Pat. No. 7,143,925 entitled“Surgical Instrument Incorporating EAP Blocking Lockout Mechanism” andfiled Jun. 21, 2005, U.S. Pat. Pub. No. 2015/0134077 entitled “SealingMaterials For Use In Surgical Stapling” and filed Nov. 8, 2013, entitled“Sealing Materials for Use in Surgical Procedures, and filed on Nov. 8,2013, U.S. Pat. Pub. No. 2015/0134076, entitled “Hybrid AdjunctMaterials for Use in Surgical Stapling,” and filed on Nov. 8, 2013, U.S.Pat. Pub. No. 2015/0133996, entitled “Positively Charged ImplantableMaterials and Method of Forming the Same,” and filed on Nov. 8, 2013,U.S. Pat. Pub. No. 2015/0129634, entitled “Tissue Ingrowth Materials andMethod of Using the Same,” and filed on Nov. 8, 2013, U.S. Pat. Pub. No.2015/0133995, entitled “Hybrid Adjunct Materials for Use in SurgicalStapling,” and filed on Nov. 8, 2013, U.S. patent application Ser. No.14/226,142, entitled “Surgical Instrument Comprising a Sensor System,”and filed on Mar. 26, 2014, and U.S. patent application Ser. No.14/300,954, entitled “Adjunct Materials and Methods of Using Same inSurgical Methods for Tissue Sealing,” and filed on Jun. 10, 2014, whichare hereby incorporated by reference herein in their entireties.

Implantable Adjuncts

As indicated above, various implantable adjuncts are provided for use inconjunction with surgical stapling instruments. The adjuncts can have avariety of configurations, and can be formed from various materials. Ingeneral, an adjunct can be formed from one or more of a film, a foam, aninjection molded thermoplastic, a vacuum thermoformed material, afibrous structure, and hybrids thereof. The adjunct can also include oneor more biologically-derived materials and one or more drugs. Each ofthese materials is discussed in more detail below.

An adjunct can be formed from a foam, such as a closed-cell foam, anopen-cell foam, or a sponge. An example of how such an adjunct can befabricated is from animal derived collagen, such as porcine tendon, thatcan then be processed and lyophilized into a foam structure. Examples ofvarious foam adjuncts are further described in previously mentioned U.S.Pat. No. 8,393,514 entitled “Selectively Orientable Implantable FastenerCartridge” and filed Sep. 30, 2010.

An adjunct can also be formed from a film formed from any suitablematerial or combination thereof discussed below. The film can includeone or more layers, each of which can have different degradation rates.Furthermore, the film can have various regions formed therein, forexample, reservoirs that can releasably retain therein one or moremedicants in a number of different forms. The reservoirs having at leastone medicant disposed therein can be sealed using one or more differentcoating layers which can include absorbable or non-absorbable polymers.The film can be formed in various ways, for example, it can be anextruded or a compression molded film.

An adjunct can also be formed from injection molded thermoplastic or avacuum thermoformed material. The adjunct can also be a fiber-basedlattice which can be a woven fabric, knitted fabric or non-woven fabricsuch as a melt-blown, needle-punched or thermal-constructed loose wovenfabric. An adjunct can have multiple regions that can be formed from thesame type of lattice or from different types of lattices that cantogether form the adjunct in a number of different ways. For example,the fibers can be woven, braided, knitted, or otherwise interconnectedso as to form a regular or irregular structure. The fibers can beinterconnected such that the resulting adjunct is relatively loose.Alternatively, the adjunct can include tightly interconnected fibers.The adjunct can be in a form of a sheet, tube, spiral, or any otherstructure that can include compliant portions and/or more rigid,reinforcement portions. The adjunct can be configured such that certainregions thereof can have more dense fibers while others have less densefibers. The fiber density can vary in different directions along one ormore dimensions of the adjunct, based on an intended application of theadjunct.

The adjunct can also be a hybrid construct, such as a laminate compositeor melt-locked interconnected fiber. Examples of various hybridconstruct adjuncts are further described in U.S. Pat. Pub. No.2013/0146643 entitled “Adhesive Film Laminate” and filed Feb. 8, 2013,and in U.S. Pat. No. 7,601,118 entitled “Minimally Invasive MedicalImplant And Insertion Device And Method For Using The Same” and filedSep. 12, 2007, which are hereby incorporated by reference in theirentireties.

Materials

The adjuncts in accordance with the described techniques can be formedfrom various materials. The materials can be used in various embodimentsfor different purposes. The materials can be selected in accordance witha desired therapy to be delivered to tissue so as to facilitate tissuein-growth. The materials described below can be used to form an adjunctin any desired combination.

The materials can include bioabsorbable and biocompatible polymers,including homopolymers and copolymers. Non-limiting examples ofhomopolymers and copolymers include p-dioxanone (PDO or PDS),polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA),polycaprolactone (PCL), trimethylene carbonate (TMC), and polylacticacid (PLA), poly(glycolic acid-co-lactic acid) (PLA/PGA) (e.g., PLA/PGAmaterials used in Vicryl, Vicryl Rapide, PolySorb, and Biofix),polyurethanes (such as Elastane, Biospan, Tecoflex, Bionate, andPellethane fibers), polyorthoesters, polyanhydrides (e.g., Gliadel andBiodel polymers), polyoxaesters, polyesteramides, and tyrosine-basedpolyesteramides. The copolymers can also include poly(lacticacid-co-polycaprolactone) (PLA/PCL), poly(L-lacticacid-co-polycaprolactone) (PLLA/PCL), poly(glycolic acid-co-trimethylenecarbonate) (PGA/TMC) (e.g., Maxon), Poly(glycolic acid-co-caprolactone)(PCL/PGA) (e.g., Monocryl and Capgly), PDS/PGA/TMC (e.g., Biosyn),PDS/PLA, PGA/PCL/TMC/PLA (e.g., Caprosyn), and LPLA/DLPLA (e.g.,Optima).

An adjunct can also include active agents, such as active cell culture(e.g., diced autologous tissue, agents used for stem cell therapy (e.g.,Biosutures and Cellerix S.L.), hemostatic agents, and tissue healingagents. Non-limiting examples of hemostatic agents can include cellulosesuch as oxidized Regenerated Cellulose (ORC) (e.g., Surgicel andInterceed), fibrin/thrombin (e.g., Thrombin-JMI, TachoSil, Tiseel,Floseal, Evicel, TachoComb, Vivostat, and Everest), autologous plateletplasma, gelatin (e.g., Gelfilm and Gelfoam), hyaluronic acid such asmicrofibers (e.g., yarns and textiles) or other structures based onhyaluronic acid, or hyaluronic acid-based hydrogels. The hemostaticagents can also include polymeric sealants such as, for example, bovineserum albumin and glutarldehyde, human serum albumin and polyethylenecross-linker, and ethylene glycol and trimethylene carbonate. Thepolymeric sealants can include FocalSeal surgical sealant developed byFocal Inc.

The adjuncts described herein can releasably retain therein at least onemedicant that can be selected from a large number of differentmedicants. Medicants include, but are not limited to, drugs or otheragents included within, or associated with, the adjunct that have adesired functionality. The medicants include, but are not limited to,for example, antimicrobial agents such as antibacterial and antibioticagents, antifungal agents, antiviral agents, anti-inflammatory agents,growth factors, analgesics, anesthetics, tissue matrix degenerationinhibitors, anti-cancer agents, hemostatic agents, and other agents thatelicit a biological response.

Non-limiting examples of antimicrobial agents include Ionic Silver,Aminoglycosides, Streptomycin, Polypeptides, Bacitracin, Triclosan,Tetracyclines, Doxycycline, Minocycline, Demeclocycline, Tetracycline,Oxytetracycline, Chloramphenicol, Nitrofurans, Furazolidone,Nitrofurantoin, Beta-lactams, Penicillins, Amoxicillin, Amoxicillin+,Clavulanic Acid, Azlocillin, Flucloxacillin, Ticarcillin,Piperacillin+tazobactam, Tazocin, Biopiper TZ, Zosyn, Carbapenems,Imipenem, Meropenem, Ertapenem, Doripenem, Biapenem,Panipenem/betamipron, Quinolones, Ciprofloxacin, Enoxacin, Gatifloxacin,Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic Acid,Norfloxacin, Sulfonamides, Mafenide, Sulfacetamide, Sulfadiazine, SilverSulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole,Sulfasalazine, Sulfisoxazole, Bactrim, Prontosil, Ansamycins,Geldanamycin, Herbimycin, Fidaxomicin, Glycopeptides, Teicoplanin,Vancomycin, Telavancin, Dalbavancin, Oritavancin, Lincosamides,Clindamycin, Lincomycin, Lipopeptide, Daptomycin, Macrolides,Azithromycin, Clarithromycin, Erythromycin, Roxithromycin,Telithromycin, Spiramycin, Oxazolidinones, Linezolid, Aminoglycosides,Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin,Paromycin, Paromomycin, Cephalosporins, Ceftobiprole, Ceftolozane,Cefclidine, Flomoxef, Monobactams, Aztreonam, Colistin, and Polymyxin B.

Non-limiting examples of antifungal agents include Triclosan, Polyenes,Amphotericin B, Candicidin, Filipin, Hamycin, Natamycin, Nystatin,Rimocidin, Azoles, Imidazole, Triazole, Thiazole, Allylamines,Amorolfin, Butenafine, Naftifine, Terbinafine, Echinocandins,Anidulafungin, Caspofungin, Micafungin, Ciclopirox, and Benzoic Acid.

Non-limiting examples of antiviral agents include uncoating inhibitorssuch as, for example, Amantadine, Rimantadine, Pleconaril; reversetranscriptase inhibitors such as, for example, Acyclovir, Lamivudine,Antisenses, Fomivirsen, Morpholinos, Ribozymes, Rifampicin; andvirucidals such as, for example, Cyanovirin-N, Griffithsin, Scytovirin,α-Lauroyl-L-arginine ethyl ester (LAE), and Ionic Silver.

Non-limiting examples of anti-inflammatory agents include non-steroidalanti-inflammatory agents (e.g., Salicylates, Aspirin, Diflunisal,Propionic Acid Derivatives, Ibuprofen, Naproxen, Fenoprofen, andLoxoprofen), acetic acid derivatives (e.g., Tolmetin, Sulindac, andDiclofenac), enolic acid derivatives (e.g., Piroxicam, Meloxicam,Droxicam, and Lomoxicam), anthranilic acid derivatives (e.g., MefenamicAcid, Meclofenamic Acid, and Flufenamic Acid), selective COX-2inhibitors (e.g., Celecoxib (Celebrex), Parecoxib, Rofecoxib (Vioxx),Sulfonanilides, Nimesulide, and Clonixin), immune selectiveanti-inflammatory derivatives, corticosteroids (e.g., Dexamethasone),and iNOS inhibitors.

Non-limiting examples of growth factors include those that are cellsignaling molecules that stimulate cell growth, healing, remodeling,proliferation, and differentiation. Exemplary growth factors can beshort-ranged (paracrine), long ranged (endocrine), or self-stimulating(autocrine). Further examples of the growth factors include growthhormones (e.g., a recombinant growth factor, Nutropin, Humatrope,Genotropin, Norditropin, Saizen, Omnitrope, and a biosynthetic growthfactor), Epidermal Growth Factor (EGF) (e.g., inhibitors, Gefitinib,Erlotinib, Afatinib, and Cetuximab), heparin-binding EGF like growthfactors (e.g., Epiregulin, Betacellulin, Amphiregulin, and Epigen),Transforming Growth Factor alpha (TGF-a), Neuroregulin 1-4, FibroblastGrowth Factors (FGFs) (e.g., FGF1-2, FGF2, FGF11-14, FGF18, FGF15/19,FGF21, FGF23, FGF7 or Keratinocyte Growth Factor (KGF), FGF10 or KGF2,and Phenytoin), Insuline-like Growth Factors (IGFs) (e.g., IGF-1, IGF-2,and Platelet Derived Growth Factor (PDGF)), Vascular Endothelial GrowthFactors (VEGFs) (e.g., inhibitors, Bevacizumab, Ranibizumab, VEGF-A,VEGF-B, VEGF-C, VEGF-D and Becaplermin).

Additional non-limiting examples of the growth factors includecytokines, such as Granulocyte Macrophage Colony Stimulating Factors(GM-CSFs) (e.g., inhibitors that inhibit inflammatory responses, andGM-CSF that has been manufactured using recombinant DNA technology andvia recombinant yeast-derived sources), Granulocyte Colony StimulatingFactors (G-CSFs) (e.g., Filgrastim, Lenograstim, and Neupogen), TissueGrowth Factor Beta (TGF-B), Leptin, and interleukins (ILs) (e.g., IL-la,IL-1b, Canakinumab, IL-2, Aldesleukin, Interking, Denileukin Diftitox,IL-3, IL-6, IL-8, IL-10, IL-11, and Oprelvekin). The non-limitingexamples of the growth factors further include erythropoietin (e.g.,Darbepoetin, Epocept, Dynepo, Epomax, NeoRecormon, Silapo, andRetacrit).

Non-limiting examples of analgesics include Narcotics, Opioids,Morphine, Codeine, Oxycodone, Hydrocodone, Buprenorphine, Tramadol,Non-Narcotics, Paracetamol, acetaminophen, NSAIDS, and Flupirtine.

Non-limiting examples of anesthetics include local anesthetics (e.g.,Lidocaine, Benzocaine, and Ropivacaine) and general anesthetic.

Non-limiting examples of tissue matrix degradation inhibitors thatinhibit the action of metalloproteinases (MMPs) and other proteasesinclude MMP inhibitors (e.g., exogenous MMP inhibitors,hydroxamate-based MMP inhibitors, Batimastat (BB-94), Ilomastat(GM6001), Marimastat (BB2516), Thiols, Periostat (Doxycycline), SquaricAcid, BB-1101, Hydroxyureas, Hydrazines, Endogenous,Carbamoylphosphates, Beta Lactams, and tissue Inhibitors of MMPs(TIMPs)).

Non-limiting examples of anti-cancer agents include monoclonialantibodies, bevacizumab (Avastin), cellular/chemoattractants, alkylatingagents (e.g., Bifunctional, Cyclophosphamide, Mechlorethamine,Chlorambucil, Melphalan, Monofunctional, Nitrosoureas and Temozolomide),anthracyclines (e.g., Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mitoxantrone, and Valrubicin), cytoskeletal disrupters (e.g., Paclitaxeland Docetaxel), epothilone agents that limit cell division by inhibitingmicrotubule function, inhibitor agents that block various enzymes neededfor cell division or certain cell functions, histone deacetylaseinhibitors (e.g., Vorinostat and Romidepsin), topoisomerase I inhibitors(e.g., Irinotecan and Topotecan), topoisomerase II inhibitors (e.g.,Etoposide, Teniposide, and Tafluposide), kinase inhibitors (e.g.,Bortezomib, Erlotinib, Gefitinib, Imatinib, Vemurafenib, andVismodegib), nucleotide analogs (e.g., Azacitidine, Azathioprine,Capecitabine, Cytarabine, Doxifluridine, Fluorouracil, 5-FU, Adrucil,Carac, Efudix, Efudex, Fluoroplex, Gemcitabine, Hydroxyurea,Mercaptopurine, and Tioguanine), peptide antibiotic agents that cleaveDNA and disrupt DNA unwinding/winding (e.g., Bleomycin and Actinomycin),platinum-based anti-neoplastic agents that cross link DNA which inhibitsDNA repair and/or synthesis (e.g., Carboplatin, Cisplatin, Oxaliplatin,and Eloxatin), retinoids (e.g., Tretinoin, Alitretinoin, andBexarotene), vinca alkaloids gents that inhibit mitosis and microtubuleformation (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine),anti-ileus agents, pro-motility agents, immunosuppresants (e.g.,Tacrolimus), blood aspect modifier agents (e.g., Vasodilator, Viagra,and Nifedipine), 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductaseinhibitors (e.g., Atorvastatin), and anti-angiogenesis agents.

Exemplary medicants also include agents that passively contribute towound healing such as, for example, nutrients, oxygen expelling agents,amino acids, collageno synthetic agents, Glutamine, Insulin, Butyrate,and Dextran. Exemplary medicants also include anti-adhesion agents,non-limiting examples of which include Hyaluronic acid/Carboxymethylcellulose (seprafilm), Oxidized Regenerated Cellulose (Interceed), andIcodextrin 4% (Extraneal, Adept).

Drug Release

An adjunct in accordance with the described techniques can be associatedwith at least one medicant in a number of different ways, so as toprovide a desired effect, such as on tissue in-growth, in a desiredmanner. The at least one medicant can be configured to be released fromthe adjunct in multiple spatial and temporal patterns to trigger adesired healing process at a treatment site. The medicant can bedisposed within, bonded to, incorporated within, dispersed within, orotherwise associated with the adjunct. For example, the adjunct can haveone or more regions releasably retaining therein one or more differentmedicants. The regions can be distinct reservoirs of various sizes andshapes and retaining medicants therein in various ways, or otherdistinct or continuous regions within the adjuncts. In some aspects, aspecific configuration of the adjunct allows it to releasably retaintherein a medicant or more than one different medicant.

Regardless of the way in which the medicant is disposed within theadjunct, an effective amount of the at least one medicant can beencapsulated within a vessel, such as a pellet which can be in the formof microcapsules, microbeads, or any other vessel. The vessels can beformed from a bioabsorbable polymer.

Targeted delivery and release of at least one medicant from an adjunctcan be accomplished in a number of ways which depend on various factors.In general, the at least one medicant can be released from the adjunctmaterial as a bolus dose such that the medicant is releasedsubstantially immediately upon delivery of the adjunct material totissue. Alternatively, the at least one medicant can be released fromthe adjunct over a certain duration of time, which can be minutes,hours, days, or more. A rate of the timed release and an amount of themedicant being released can depend on various factors, such as adegradation rate of a region from which the medicant is being released,a degradation rate of one or more coatings or other structures used toretains the medicant within the adjuncts, environmental conditions at atreatment site, and various other factors. In some aspects, when theadjunct has more than one medicant disposed therein, a bolus doserelease of a first medicant can regulate a release of a second medicantthat commences release after the first medicant is released. The adjunctcan include multiple medicants, each of which can affect the release ofone or more other medicants in any suitable way.

Release of at least one medicant as a bolus dose or as a timed releasecan occur or begin either substantially immediately upon delivery of theadjunct material to tissue, or it can be delayed until a predeterminedtime. The delay can depend on a structure and properties of the adjunctor one or more of its regions.

An adjunct material can be configured to have a structure thatfacilitates distribution of effective amounts of one or more medicantscarried within the adjunct to provide a desired effect. For example, thetargeted delivery of the medicants can be accomplished by incorporatingthe medicants into regions (e.g., reservoirs such as pores or otherstructures) within the adjunct formed in a pattern that allows a certainspatial distribution of the medicants upon their delivery. The medicantsdisposed within the reservoir can be incorporated into distinct vessels.A reservoir can include more than one type of different medicants. Theone or more medicants can be eluted from the adjunct in a homogeneousmanner or in heterogeneous spatial and/or temporal manner to deliver adesired therapy. The structure of the adjunct and the way in which themedicants are released therefrom can be used to influence or controltissue re-growth. Moreover, the tissue regrowth can be encouraged incertain locations at the treatment site and discouraged at otherlocations at the treatment site.

FIG. 6 through FIG. 8 illustrate a biocompatible adjunct 100 havingmultiple pores carrying different medicants that are encapsulated withinthe pores disposed at different locations and using different absorbablecoatings. The coatings can absorb, dissolve or otherwise disintegrate atdifferent times after delivery of the adjunct 100 to a treatment siteand staple deployment so as to allow the medicants to also release atdifferent times and in different directions. Thus, the medicants can bereleased from the adjunct 100 in a non-homogeneous manner. For example,one of the medicants can be released immediately after delivery and/orstaple deployment whereas one or more of other medicants can be releasedat a later time, such as over a predetermined release profile. Therelease of these subsequently released medicants can be controlled by ordepend upon the release of the first medicant. The opposite sides of theadjunct 100 can be covered by coatings (or be formed of materials)having different absorption rates such that certain medicant(s) arereleased on one side of the adjunct while other medicant(s) are releasedon another side of the adjunct. This provides a more controlled andtargeted way of delivering therapies to tissue.

In this example, the adjunct 100 is in the form of a layer havingmultiple porous regions, two of which are shown by way of example aspores 101, 103. As shown in FIG. 6, the porous regions 101, 103 carryrespective first and second medicants 102, 104 which can be differentmedicants. It should be appreciated that the adjunct 100 has multipleporous regions which can carry the medicants 102, 104 in an alternatingmanner or in any other patterns.

As shown in FIG. 6, a first side 100 a of the adjunct 100 has coatingsA, C such that the coating A seals the porous region 101 with the firstmedicant 102 and the coating C seals the porous region 103 with thesecond medicant 104. A second, opposite side 100 b of the adjunct 100 iscovered by a coating B. In the illustrated example, the coatings A, B, Cthat create a barrier that affects release of a medicant can be selectedsuch that the coating A absorbs first after the staple deployment, thecoating B absorbs after the coating A has been at least partiallyabsorbed, and the coating C is not absorbable.

As shown in FIG. 7, after the delivery and/or staple deployment, thecoating A is first absorbed so as to allow the first medicant 102 to bereleased from the porous region 101 at the first side 100 a of theadjunct 100. For example, if the first side 100 a is a tissue-contactingsurface, the first medicant 102 can be a medicant that promotes healingat the treatment site. Subsequently, after a certain time period, thecoating B can be absorbed so as to allow the second medicant 104 to bereleased from the porous region 103 at the second side 100 b of theadjunct 100, as shown in FIG. 8. For example, if the second side 100 bis a non-tissue-contacting surface, the second medicant 104 can be amedicant that prevents adhesion. As also shown in FIG. 8, the coating Cseals the porous region 103 at the first side 100 a and thus preventsthe second medicant 104 from being released at the first side 100 a ofthe adjunct 100. Although in this example the coating C is notabsorbable, it can alternatively be absorbable after the coating B hasbeen absorbed and the second medicant 104 can been released at thesecond side 100 b. It should be appreciated that, to allow a porousregion to be exposed and a medicant to release, a coating can beabsorbed in its entirety or at least partially. A rate of absorption ofa coating can control a rate of release of a medicant.

A person skilled in the art will appreciate that more than two differentmedicants can be releasably incorporated into different porous regionsor other structures within an adjunct. The medicants can be retainedwithin the adjunct using various coatings that can be selected so as tocontrol rate and direction of release of the medicants.

An adjunct can include regions (e.g., pores or other reservoirs)releasably retaining a plurality of vessels, such as micro beads orother vessels, that have one or more medicants encapsulated therein.FIG. 9 through FIG. 11 illustrate an adjunct 108 including at least onemedicant encapsulated in a plurality of vessels that are releasablyretained by respective regions that regulate the dispersion of thevessels from the adjunct. The vessels can be micro capsules, microbeads, or any other types of vessels of a suitable size and shape. Eachvessel can have an absorbable outer layer that can degrade and thusrelease a medicant retained within that vessel once the vessels arereleased from an adjunct. The adjunct can be used to deliver medicantsin a non-homogeneous manner with respect to at least time of release andlocation of release.

As shown in FIG. 9, the adjunct 108 has multiple reservoirs or regions,five of which are shown as regions 109 a, 111 a, 113 a, 109 b, 111 bthat carry respective vessels 110, 112, 114, 110, 112. Thus, as shownschematically in FIG. 9, the regions 109 a, 109 b carry the same firsttype of vessels 110, the regions 111 a, 111 b carry the same second typeof vessels 112, and the region 113 a carries a third type of vessels114.

As shown in FIG. 9, on a first side 108 a of the adjunct 108, a layer ofcoating B1 seals the regions 111 a, 113 a and the region 111 b. A layerof a coating A1 is disposed over the entire first side 108 a and coversthe layers of the coating B1. On a second, opposite side 108 b of theadjunct 108, a layer of the coating B1 seals the region 109 a andanother layer of the coating B1 seals the region 109 b. A layer of acoating C1 seals the region 113 a on the second side 108 b. Similar tothe first side 108 a, the entire second side 108 b is covered by thecoating A1.

In this example, the coatings A1, B1, C1 have different degradation orabsorption rates such that the coating A1 begins to absorb first, upon adelivery of the adjunct to tissue, the coating B1 absorbs after thecoating A1 is at least partially absorbed, and the coating C1 is notabsorbable. The coating A1 can be selected such that it absorbssubstantially immediately after the delivery of the adjunct to tissue orat some later time. The coating A1 can be absorbed before the coating B1because the coating A1 is disposed on the surface of the adjunct and istherefore more accessible to water and/or other agents at a treatmentside. Other properties of the coating A1 can contribute to itsabsorption rate additionally or alternatively.

Because of the different absorption characteristics of the coating used,the coating A1 absorbs so as to release the first medicant 110 from theregions 109 a, 109 b at the first side 108 a and to release the secondmedicant 112 from the regions 111 a, 111 b at the second side 108 b, asshown in FIG. 10. As also shown in FIG. 10, the layers of the coating B1remain associated with the adjunct 108. As shown in FIG. 11, after thefirst medicant 110 is released at the first side 108 a and the secondmedicant 112 is released at the second side 108 b, the coating B1absorbs so as to release the third medicant 114 from the region 113 a atthe first side 108 a. In this way, different medicants can be deliveredat appropriate times to desired locations in tissue being treated. Itshould be appreciated that an adjunct can have any suitable pattern ofregions releasably retaining various medicants to create a desiredhealing process/profile.

In some aspects, alternatively or in addition to using various coatings,an adjunct can be in a form of a fiber lattice having regions withdifferent absorption characteristics. For example, each of the regionscan be in the form of fiber lattices having different absorption rates.A medicant associated with a fiber lattice can be released as the fiberlattice disintegrates. Because of the heterogeneous degradation ofabsorbable polymers forming the adjunct, the adjunct can be configuredsuch that one or more medicants associated therewith can release invarious spatial and temporal patterns. The medicant can be incorporatedinto pellets having a dissolvable coating (e.g., like a gobstopper) suchthat, as the coating is disintegrated, the medicant can be distributedas a bolus dose or as a time release dosage.

FIG. 12 through FIG. 14 illustrate an adjunct 116 having first (top) andsecond (bottom) layers 118, 120 formed from absorbable polymers havingdifferent degradation rates. For example, the first layer 118 can be alow molecular weight absorbable polymer that absorbs during a first timeperiod after the adjunct 116 is delivered to tissue and the second layer120 can be a high molecular weight absorbable polymer that absorbsduring a second time period after the first time period is completed.The first and second layers 118, 120 can be formed from differentpolymers or from the same type of polymer that is treated so as to formlayers or other structures having different degradation properties.

In the example of FIG. 12 through FIG. 14, the first layer 118 has afirst medicant 119 present therein, and the second layer 120 has secondmedicant 121 present therein. It should be appreciated, however, thateach of the first and second layers 118, 120 can include more than onetype of different medicant. The medicants can be retained in associationwith the first and second layers 118, 120 in a number of suitable ways.The first medicant 119 can be released first due to absorption of thefirst layer 118, as shown in FIG. 13 where the first layer 118 is shownpartially disintegrated such that the pellets containing the firstmedicant 119 are being released. As shown, the first layer 118 begins toabsorb from its surface that is more accessible to water and otheragents than portions of the first layer 118 removed farther from thesurface. After the first layer 118 has been entirely or partiallyabsorbed, the second layer 120 can commence to disintegrate from itssurface so as to release pellets harboring the second medicant 121, asshown in FIG. 14 where the second layer 120 is shown partiallydisintegrated and the pellets containing the second medicant 121 arebeing released from the adjunct 116.

In some aspects, an adjunct releasably retaining one or more medicantscan be configured such that one or more regions of the adjunctdisintegrate due to effects of temperature, pH, light, or otherenvironmental factors so as to release the medicant(s). Alternatively,the adjunct can break under the strain exerted upon one or more of itsportions. FIG. 15 through FIG. 17 illustrate an adjunct 122 having abody 123 retaining a medicant 124, a porous layer 125 disposed over thebody 123, and an absorbable outer film layer 126 disposed over theporous layer 125. The medicant 124 can be in the form of pellets (e.g.,solid micro-capsules or micro-beads or other vessels) releasablycarrying one or more medicants.

In the example illustrated, in its original configuration, the adjunct122 has a first width X1, as shown in FIG. 15. In such configuration,the outer film layer 126 restrains the porous layer 125 and pores in theporous layer 125 have a size that does not allow the medicant 124 toescape the adjunct 122. However, when the adjunct 122 is delivered totissue and the outer film layer 126 thus becomes exposed to pH,temperature, various agents, and/or other environmental conditions atthe treatment site, the absorbable outer film layer 126 can begin todisintegrate, as shown by a tear or opening 127 in the film layer 126 inFIG. 16. Additionally or alternatively, the outer film layer 126 canbreak upon strain due to deployment of staples or other mechanicalstrain on the adjunct 122.

Regardless of the specific factors that result in disintegration orbreaking of the outer film layer 126, the adjunct 122 can swell orotherwise alter its conformation such that its width increases from theoriginal width X1 to a larger width X2. As also shown in FIG. 15, thesize of the pores of porous layer 125 increases, allowing the pores'content, the pellets carrying the medicant 124, to pass through theenlarged pores and to be thus released from the adjunct 122.

A period of time during which the adjunct body 123 expands and thepellets with the medicant 124 are released can vary based on anabsorption rate of the outer film 126, properties of the adjunct body123, characteristics of the environment to which the adjunct 122 isdelivered, and other factors. After a certain time period, the outerfilm layer 126 can disintegrate and the adjunct 122 can expand furtherto have a width X3 such that the entirety or substantially the entiretyof the medicant 124 becomes released from the body 123 to deliverappropriate therapy or achieve the desired effect, as shown in FIG. 17.The adjunct 122 can be formed from at least one absorbable polymer(e.g., gelatin, cellulose, etc.) that regulates dispersion of thevessels. Thus, the adjunct 122 can act as a space filler that creates atemporary seal at a treatment site and is then dissolved to besubsequently replaced with tissue.

FIG. 18 and FIG. 19 illustrate another example of an adjunct 128releasably retaining different medicants and configured to release themedicants in a non-homogeneous manner. The adjunct 128 can be configuredto release the medicants due the effects of temperature, pH, variousagents, and/or other environmental factors upon the adjunct 128. Theadjunct 128 can change a conformation of one or more of its portions inresponse to the environmental factors. As shown in FIG. 18, the adjunct128 can have multiple regions or reservoirs two of which, first andsecond reservoirs 130, 132 carrying first and second medicants 131, 133,respectively, are shown. The reservoirs 130, 132 can be in the form oftubes, cavities, holes, or any other structures. The first reservoir 130is sealed by a first coating A2 at a first side 128 a of the adjunct 128and by a second coating B2 at a second side 128 b of the adjunct 128.The second reservoir 131 is sealed by the second coating B2 at the firstside 128 a and by the first coating A2 at the second side 128. In thisexample, the first and second coatings A2, B2 are selected such that thefirst coating A2 and its properties and/or configuration can be alteredby the effects of temperature, pH, active agents, and/or other factorsand thus open a reservoir that it seals. For example, the first coatingA2 can swell, soften, or otherwise become altered.

Accordingly, as shown in FIG. 19, upon the delivery of the adjunct 128to a treatment site, the first coating A2 can change its configurationsuch that it no longer seals the reservoir 130 at the first side 128 aof the adjunct 128 and it no longer seals the reservoir 132 at thesecond side 128 b of the adjunct 128. As a result, the first and secondmedicants 131, 133 are released at the first and second sides 128 a, 128b of the adjunct, respectively, as also shown in FIG. 19. The secondcoating B2 remains in place at least until the entirety of the medicantsare released into desired tissue locations, such preventing the releaseof the medicants.

In some aspects, the adjunct can be in the form of fibers or otherstructural components associated with one or more viscous fluidcomponents (e.g., vessels) retaining the medicant. The viscous componentcan be in a dry form (e.g., in a freeze-dried powder form) and it canre-hydrate upon deployment of the adjunct. As the viscous componentrehydrates, it can open and thus release a medicant. Additionally oralternatively, the vessel retaining the medicant can be disrupted bystrain such as, for example, mechanical breaking imposed thereon by thestaples or other means.

FIG. 20 and FIG. 21 illustrate an adjunct 140 in the form of multiplefibers, three of which are denoted by way of example as fibers 142, 144,146. As shown, each of the fibers 142, 144, 146 is associated with arespective one of vessels 143, 145, 147 retaining a medicant. Thevessels 143, 145, 147 can retain the same or different medicants. In theillustrated example, the vessels 143, 145, 147 are in the form ofirregularly shaped rounded beads having different sizes, however theycan be shaped in any other manner and can have various sizes. Thevessels can be applied to the fibers as a powder or they can be bonded,anchored to, or otherwise associated with the fiber strands. The vesselscan remain associated with the fibers or they can be released from thefibers to thus deliver a desired treatment using the adjunct.

As shown in FIG. 21, when strain is applied to the adjunct 140, which isschematically shown by arrows 141, the fibers can deform and vessels canbreak and release the medicant incorporated therein. The magnitude ofthe strain can control rates of release of the medicants. For example,as shown in FIG. 21, the vessel 143 is broken and a medicant 148 isbeing released. In some aspects, the vessels can be broken at differenttimes, depending on their size and/or other properties. In this example,the vessel 143 can be broken first to release the medicant 148 retainedtherein, as shown in FIG. 21, after which the smaller vessel 145 andthen even smaller vessel 147 can break thus releasing respectivemedicants at different times (not shown). However, depending on theapplied pressure and other factors, one or more vessels can breaksimultaneously. Furthermore, as mentioned above, the vessels 143, 145,147 can absorb at different times so as to release the respectivemedicants at different times.

In some aspects, an adjunct can have various surface textures of itsfibers and it can release one or more medicants in various ways toinfluence or control re-growth of tissue. The adjunct can be deliveredby staples carrying the adjunct thereon such that the medicants releasewhen the staple is deformed upon staple deployment. For example, FIG. 22illustrates an adjunct 150 having an outer layer or coating 152encapsulating an inner layer 154 disposed over a staple 151 of asurgical device used to deliver the adjunct 150. However, in someaspects, rather than being disposed over a staple, the adjunct 150 canbe disposed over a fiber lattice which can be folded into a tubular orother shape.

A first medicant can be retained between the outer coating 152 and theinner layer 154, and a second medicant can be incorporated into theinner layer 154. The inner layer 154 can be in the form of a flexiblemesh wound over the fiber 156. When strain is applied to the adjunct 150(e.g., when the staple 151 is deformed), as schematically shown by anarrow 153 in FIG. 23, the outer coating 152 can be caused to also deformand rupture. Upon the rupture of the outer coating 152, the firstmedicant retained between the outer coating 152 and the inner layer 154can release (155) the first medicant as a bolus dose. The secondmedicant incorporated into the inner layer 154 can commence its releaseas a timed release after the first medicant is released or during thetime when the first medicant is released. The release of the secondmedicant to tissue can be regulated by the release of the firstmedicant. The second medicant can alternatively be released at a bolusdose. It should be appreciated that the adjunct 150 can include onemedicant disposed within the inner layer 154 that can release as a bolusdose.

As mentioned above, an effective amount of at least one medicantdisposed within or associated with an adjunct can be retained withindistinct vessels carried by the adjunct. The vessels can be disposedwithin one or more regions of the adjunct or otherwise associatedtherewith. FIG. 24 and FIG. 25 illustrate an example of a vessel 158 inthe form of a pellet or capsule having an outer coating 159encapsulating therewithin at least one medicant 160. In this example,the vessel 158 has a spherical shape and resembles a gobstopper.However, it should be appreciated that the vessel can have any othershape. Furthermore, in some exemplary implementations, the outer coating159 can encapsulate an inner region including at least one bioabsorbablepolymer having at least one medicant incorporated therein. The vessels158 can include multiple layers having different degradation rates andreleasably retaining therein one or more medicants. Each of the layerscan retain a different medicant, or two or more of the layers can carrythe same medicant.

When a strain is applied to the vessel 158 as schematically shown by anarrow 161 in FIG. 25, the outer coating 159 can break or rupture suchthat its contents in the form of the at least one medicant 160 arereleased. Additionally or alternatively, the outer coating 159 canabsorb, dissolve or otherwise disintegrate upon exposure of the vessel158 to one or more environmental conditions such that the at least onemedicant 160 is released from the vessel 158.

FIG. 26 and FIG. 27 illustrate an example of an adjunct 162 in the formof a fiber lattice having a certain conformation that is changeable,such as by the action of water and/or other agents that the adjunct issubjected to at the treatment site. As shown in FIG. 26, the adjunct 162having a shape of a tightly wound spiral can retain therein one or morevessels carrying a medicant 164. The medicant 164 can be retained inassociation with the adjunct 162 by being held tightly by fibers of theadjunct. For example, the medicant can include a multilayeredmedicant/absorbable polymer structure where an outermost one of thelayers includes an absorbable polymer that can be bound to the fibers ofthe adjunct, e.g., bonding of one absorbable polymer to anotherabsorbable polymer, as will be appreciated by a person skilled in theart.

When the adjunct 162 is delivered at the treatment site, the woundfibers thereof can swell and increase in length, or elongate, such thatthe distances between the fibers increase and the adjunct 162 “unwinds”and releases the medicant 164 “trapped” within the adjunct 162, as shownin FIG. 27. The fibers of the adjunct 162 can unwind such that theentire adjunct 162 adopts a different conformation, like in the exampleof FIG. 26 and FIG. 27. However, in some aspects, the fibers of theadjunct can begin to unwind or fray from an end or other surface of theadjunct.

FIG. 28 and FIG. 29 illustrate another example of an adjunct 166 havinga medicant 168 releasably retained therein. In this example, the adjunct166 is in the form of a sheet-like fiber woven mesh. As shown in FIG.28, the tight fibers of the adjunct 166 in its original configurationallow the medicant 168 to be retained therein. When the adjunct 166 isdelivered at the treatment site, water and/or other agents, shownschematically as drops 167 a, 167 b in FIG. 28, can cause the fibers toswell and elongate such that the distances between the fibers increase,as shown in FIG. 29. In this way, the medicant 168 is released, as alsoshown in FIG. 29. A person skilled in the art will appreciate that theadjunct 166 can be formed from different types of fibers. The fibers canhave different absorption rates, density, direction, patterns, size, andother properties that are selected so as to provide desired tissuere-growth. While some regions of the adjunct can be configured torelease at least one medicant so as to encourage tissue re-growth, oneor more regions of the adjunct can be configured to release at least onemedicant so as to discourage tissue re-growth.

In aspects in which at least one medicant is disposed within a vesselformed from a bioabsorbable polymer coating encapsulating the medicant,the medicant can be configured to be released from the vessel at certaintime based on various factors. The factors can include, for example, adegradation rate of the bioabsorbable polymer, a volume of the vessel, asurface area of the vessel, environmental conditions in a physiologicalenvironment surrounding the vessel and responsiveness of thebioabsorbable polymer to such conditions, a number of layers of thebioabsorbable polymer, a concentration of the medicant, and a type ofassociation between the medicant and the bioabsorbable polymer.

FIG. 30 illustrates an example of first and second vessels 170, 172 thatcan be associated with a schematically shown adjunct 171. In thisexample, the first and second vessels 170, 172 are in the form ofspherical beads. However, other types of vessels can be usedadditionally or alternatively such that the adjunct 171 can include oneor more different types of vessels carrying different types ofmedicants. The first and second vessels 170, 172 have absorbable polymerouter coatings A3, B3 that have different degradation rates whichtherefore control release of first and second medicants D1, D2encapsulated within the coatings A3, B3 in different manners. Adegradation rate of the outer coating A3 can be higher than adegradation rate of the outer coating B3. Thus, the first medicant D1 isreleased from the first vessel 170 before the second medicant D2 isreleased from the second vessel 172. For example, the first medicant D1can be an inflammatory agent that is released within 1-2 days after theadjunct 171 is delivered to a treatment site. The second medicant D2 canbe an anti-inflammatory agent that is released within 3-5 days after thedelivery of the adjunct 171. In this way, the release of the medicantsD1, D2 from the first and second vessels 170, 172 can provide a desiredeffect on tissue in-growth.

A vessel having at least one medicant encapsulated therein can havemultiple medicants associated therewith in a number of different ways.FIG. 31 illustrates an example of a vessel 174 in a form of a spherehaving multiple concentric layers each carrying a respective at leastone medicant. In this example, as shown in FIG. 31, the vessel 174 has,from the outside to the inside, four distinct layers E1, E2, E3, E4having first, second, third, and fourth medicants F1, F2, F3, F4,respectively. Each of the layers E1, E2, E3, E4 can have differentdegradation rate, thickness, density, responsiveness to environmentalconditions, and other properties that control release of the medicantsdisposed therein. For example, the outermost first layer E1 can beconfigured to degrade first such the medicant is released first, and theother layers E2, E3, E4 can be configured to degrade such that an outerlayer degrades before an inner layer does.

As each layer degrades, a respective medicant incorporated therein isreleased. It should be appreciated that the layers can be selected suchthat at least one inner layer can start to degrade after only a portionof at least one outer layer has been degraded. The medicants F1, F2, F3,F4 disposed within the multi-layer vessel 174 can be different or atleast some of the medicants can be the same. The medicants can bereleased as a bolus dose or in other manners. For example, the firstmedicant F1 disposed within the first layer E1 can be released as abolus dose substantially immediately upon delivery of an adjunctretaining the vessel 174 to tissue. Release of the second medicant F2disposed within the second layer E2 can be regulated by the release ofthe first medicant F1.

A spatial distribution of medicants in an adjunct can vary depending ona type of the medicants and a desired effect on tissue in-growth.Targeted delivery of the medicants can be accomplished in a number ofways. For example, an adjunct can be configured to release one or moremedicants in a heterogeneous manner such that various medicants can bedelivered to tissue at different times, to facilitate desired healing.Different portions of the adjunct can be formed from different materialsor form the same material treated so as to have different absorptionrates.

FIG. 32 illustrates an adjunct 176 in the form of a laminate includingheterogeneous portions or layers having different degradation rates andincorporating different medicants. As shown, the adjunct 176 has a toplayer or portion 178 and a bottom layer or portion 180 that havedifferent degradation rates. Furthermore, each of the top and bottomportions 178, 180 can have various portions having degradation ratesthat vary in a distinct or continuous manner. The degradation rates canvary across the adjunct in a number of suitable ways that depend on adesired treatment effect to be provided by the adjunct.

In the example of FIG. 32, the top portion 178 of the adjunct 176 hastwo portions 178 a, 178 b having different degradation rates. The bottomportion 180 has two portions 180 a, 180 b having different degradationrates. Each of the portions can include a different medicant such that,as a portion degrades, a respective medicant is eluted or released. Thedegradation rates and distribution of the medicants within one or moreof the portions 178 a, 178 b, 180 a, 180 b can further vary in adistinct or continuous manner such that the adjunct 176 can provide anelution profile shown in a graph 177 in FIG. 32. As shown, a centralarea 182 of the adjunct 176 centered around a mid-portion 179 thereofhas an increased elution rate of one or more medicants that peaks at themid-portion 179, whereas smaller amount of the medicant(s) is elutedfrom opposite sides of the adjunct 176 along its length L. The increasedelution rate can be due to properties of the adjunct 176 at the centralarea 182 and the concentration of the medicants.

As further shown in FIG. 32, the adjunct 176 is configured to releasemedicants in different elution profiles along the length L thereof andalong a width W thereof. For example, the medicants can be releasedalong the width W as a bolus dose and along the length as a time-releasedose. Release of one or more of the medicants can regulate release of atleast one other of the medicants. However, the medicants can be releasedin any other manner, depending on a desired treatment to be delivered.

FIG. 33 illustrates another example of an adjunct 184 having top andbottom layers or portions 186, 188. Similar to the adjunct 176 in FIG.32, each of the top and bottom portions 186, 188 of the adjunct 184 canhave different medicants disposed therein. Thus, as shown in FIG. 33,the top portion 186 can have first and second medicants G1 and G2, atrespective portions thereof. The bottom portion 188 can have third andfourth medicants G3 and G4 at respective portions thereof disposed suchthat the third medicant G3 is in a portion disposed over a portioncarrying the fourth medicant G4, as also shown in FIG. 34.

FIG. 35 illustrates an example of a portion of an adjunct 185 that canbe similar to adjunct 176 (FIG. 32) or adjunct 184 (FIG. 33). As shownin FIG. 35, the adjunct 185 can have side-to-side portions 185 a, 185 bhaving different medicants G5, G6 disposed therein. FIG. 36 illustratesanother example of a portion of an adjunct 187 having an inner portion187 a and an outer portion 187 b having different medicants G7, G8disposed therein.

In some aspects, elution rates of at least one medicant from an adjuncthaving one or more distinct portions formed from at least onebioabsorbable polymer can depend on a position of the portions withinthe adjunct, a degradation rate of the at least one bioabsorbablepolymer, responsiveness of the at least one bioabsorbable polymer toenvironmental conditions, and an overall configuration of the adjunct.

FIG. 37 illustrates an example of an adjunct 190 in a form of a cylinderthat has outer and inner concentric layers 191, 192 which can be formedfrom different types of absorbable polymer and can have differentthickness and other properties. The outer and inner layers 191, 192 canhave different medicants B4, A4 disposed therein and that can bereleased from the respective layers 191, 192 at different times and atdifferent rates. In this example, an innermost cavity 193 lined by theinner layer 192 can be empty. The medicant A4 can be configured tocommence to release before the medicant B4 is released. It should beappreciated that, in some aspects, the outer and inner layers 191, 192can be disposed over a fiber.

FIG. 38 illustrates an example of a tubular adjunct 194 that hasmultiple radial portions formed from different types of absorbablepolymer. As shown, the adjunct 194 has an inner cavity 194 a having theradial portions disposed concentrically therearound. In the exampleillustrated, the portions can be formed from first and second types ofpolymer in an alternating manner, as shown by portions 195, 196 in FIG.38 formed from the first and second polymers, respectively. The portion195 formed from the first polymer has a medicant A5 disposed therein,the portion 197 formed from the second polymer has a medicant B5disposed therein, and other portions formed from the first and secondpolymers have the medicants A5, B5 disposed therein in the samealternating manner, as shown in FIG. 38. Similar to the examples before,the medicants A5, B5 can be released from the respective layers atdifferent times and at different rates. For example, the medicant A5 canbe configured to commence to release before the medicant B5 is released.

FIG. 39 illustrates an example of a tubular adjunct 197 similar toadjunct 190 (FIG. 37). As shown in FIG. 39, the adjunct 197 has outerand inner concentric layers 198, 199 which can be formed from differenttypes of absorbable polymer and can have different thickness and otherproperties. The outer and inner layers 198, 199 can have differentmedicants B6, A6 disposed therein and that can be released from therespective layers 198, 199 at different times and at different rates.For example, as shown in a graph 197 a in FIG. 39, the medicant A6 canrelease before the medicant B6 is released. Furthermore, the medicant A6can release at a higher dosage than the medicant B6, as also shown inthe graph 197 a.

In at least some implementations, a staple cartridge can include alubricant (e.g., sodium stearate or other lubricant) applied theretothat includes at least one medicant (e.g., LAE, Doxycycline, and/orother antimicrobial agent) releasable therefrom. The lubricant can beapplied to the staple cartridge as a spray and can coat the cartridgeand the staples releasably disposed therein. The lubricant including oneor more medicants may allow the medicant(s) to be applied to thestaples. In this way, the medicant(s) may be delivered to a targetedarea (e.g., along a staple line defined by the staples) where themedicant(s) may be best able to facilitate wound healing, as discussedherein. The lubricant including one or more medicants can be used withan adjunct including one or more medicants, which may facilitatetargeted wound healing.

Wound Healing

During performance of a surgical procedure, tissue of a patient can bewounded (e.g., cut, torn, punctured, etc.) in any of a variety of ways.The wounding may be an intended aspect of the surgical procedure, suchas in an anastomosis procedure and/or when tissue is cut and fastenedusing a surgical device such as a surgical stapler. The wounded tissuetypically heals over time in generally the same way for all patients.

Wound healing is traditionally considered to include four stages:hemostasis, inflammation, proliferation, and remodeling. The hemostasisstage generally involves blood clotting, e.g., stopping bleeding. Ingeneral, damaged blood vessels constrict to slow blood flow, plateletsaggregate to help seal the wound site, the platelets activate fibrin tofurther facilitate wound sealing, and a blood clot forms at the woundsite. The inflammation stage generally involves cleaning of the woundsite. In general, the immune system provides a response to the threat ofpossible infection at the wound site via signaling to defensive immunecells such as neutrophils and macrophages. The proliferation stagegenerally involves rebuilding tissue with tissue growth and angiogenesis(blood vessel growth). In general, fibroblasts arrive at the wound site,the fibroblasts lay down collagen, the fibroblasts release growthfactors that attract epithelial cells, and the epithelial cells attractendothelial cells. The remodeling stage, also referred to as amaturation stage, generally involves strengthening scar tissue at thewound site. In general, collagen fibers align and crosslink, and thescar matures to eventually fade away. Each of these four stages isdiscussed further below.

While each of wound healing's four stages involves a different aspect ofthe healing process, stages typically overlap with one another. Namely,each of the last three stages typically overlaps with its precedingstage, e.g., inflammation overlaps with hemostasis, proliferationoverlaps with inflammation, and remodeling overlaps with proliferation.The speed at which the transition between stages occurs generallyaffects the speed of overall wound healing and thus generally affectspatient recovery time, chances of complications arising, and/or patientcomfort. Similarly, the length of each of the four individual stagesgenerally affects the speed of overall wound healing and the patient'sgeneral recovery. In general, the slower the wound healing process, andin particular the longer it takes to begin the remodeling stage, themore likely that the wound will become infected, cause the patientdiscomfort, become a chronic wound, cause an ulcer, and/or developpathological scarring.

The hemostasis stage generally begins within minutes of the initialinjury, unless there are underlying clotting disorders, in which casehemostasis may be delayed. The hemostasis stage typically lasts for 30to 60 minutes before the inflammation stage begins (e.g., beforeneutrophils arrive, as discussed below) and typically ends hours afterthe injury, e.g., 2 to 6 hours post-injury. Poor hemostatic control thatresults in a longer hemostasis stage can lead to increased bleeding andtissue damage. Additionally, a prolonged hemostasis stage can result inadditional scar formation that delays the proliferation and remodelingstages.

In the hemostasis stage, injured blood vessels at the wound site aresealed. The blood vessels constrict in response to injury, e.g., inresponse to being cut, but this spasm ultimately relaxes. Bloodplatelets secrete vasoconstrictive substances to aid in this process.The platelets also form a stable clot sealing the damaged vessels. Underthe influence of adenosine diphosphate (ADP) leaking from the damagedtissue at the wound site, the blood platelets aggregate and adhere toexposed collagen. The blood platelets secrete factors, which interactwith and stimulate an intrinsic clotting cascade through the productionof thrombin, which in turn initiates the formation of fibrin fromfibrinogen. The clotting cascade occurs to achieve hemostasis, or stopblood loss by way of a fibrin clot. More particularly, the fibrin formsa mesh that strengthens the platelet aggregate into a stable hemostaticplug or clot, thereby reducing and/or preventing bleeding. The meshserves as a scaffold for invading cells, such as neutrophils,macrophages, fibroblasts, and endothelial cells, during the inflammationand proliferation stages. Additionally, the platelets secrete varioussoluble factors, such as chemokines, cytokines, and platelet-derivedgrowth factor (PDGF). This secretion generally initiates theinflammation stage of wound healing, as the soluble factors attractcells that phagocytize material (e.g., debris, microorganisms such asbacteria, and damaged tissue).

The clotting cascade occurs in the hemostasis stage just before theinflammatory stage begins. The inflammation stage typically beginswithin an hour of the injury and typically lasts for 2 to 6 days but canlast even longer, e.g., up to 10 days. The longer the inflammationstage, the more likely that additional scarring will occur, therebydelaying the proliferation and remodeling stages. During theinflammation stage, the wounded tissue can show various signs ofinflammation, such as erythema, heat, edema, pain, and functionaldisturbance. These signs can last for most or all of the inflammationstage. Accordingly, the longer the inflammation stage, the longer thetissue experiences these adverse effects of inflammation, which in turncan prolong patient discomfort and/or prolong the period of time inwhich the patient is particularly susceptible to infection. The adverseeffects of inflammation can be severe enough in some patients to causedeath. Inflammation must occur during proper wound healing, however, andits adverse effects tolerated in order for the final stages of woundhealing to commence.

In the inflammation stage, the cells attracted by the soluble factorssecreted in the hemostasis stage phagocytize material. Namely, immunecells including phagocytic cells, neutrophils, and macrophages destroymaterial in an effort to help prevent infection. The arrival ofneutrophils generally signals the start of the inflammation stage.Neutrophils typically arrive at the wound site within an hour ofwounding. The neutrophils are able to phagocytize debris andmicroorganisms and provide a first line of defense against infection.They are aided by local mast cells. Fibrin is broken down, and thedegradation products attract macrophages. Macrophages typically appear 1to 2 days post-injury. The macrophages are able to phagocytize bacteriaand provide a second line of defense against infection. The macrophagessecrete a variety of chemotactic factors and growth factors such asfibroblast growth factor (FGF), epidermal growth factor (EGF),transforming growth factor beta (TGF-β), and interleukin-1 (IL-1), whichare traditionally recognized as directing the subsequent proliferationand remodeling stages. In other words, the macrophages releaseangiogenic substances to help begin the proliferation stage to stimulatecapillary growth and granulation, thereby setting the stage for theremodeling stage. Lymphocytes (e.g., T lymphocytes) attracted to thewound site typically appear at the wound site after the macrophagesappear.

The proliferation stage typically begins 2 to 5 days post-injury andtypically lasts for 2 to 21 days. In the proliferation stage, themacrophages' secretion induces the proliferation of fibroblasts. Thefibroblasts enter the wound site and form an extracellular matrix (ECM)by excreting collagen and fibronectin. The wound is thus “rebuilt” withnew granulation tissue that includes the collagen and the ECM into whicha new network of blood vessels develop, a process traditionally known asangiogenesis. The collagen increases the strength of the wound.Accordingly, the sooner collagen can be produced, e.g., the sooner thatfibroblasts enter the wound area, the sooner the wound can gain strengthand thereby be less likely to cause any number of problems such asinfection and patient discomfort.

Concurrent with the ECM formation, epithelial cells (e.g.,keratinocytes) migrate from the wound's edge to cover the wound and forma barrier between the wound and its environment. In other words, theepithelial cells resurface the wound, in a process traditionally knownas epithelialization. The epithelial cells migrate over the granulationtissue but underneath the scab on the wound (if a scar was earlierformed). The epithelial cells must dissolve the clot, debris, and partsof the ECM in order to properly migrate over the wound. To facilitatetheir migration, the epithelial cells secrete a plasminogen activator,which activates plasminogen, turning it into plasmin to dissolve theclot, debris, and parts of the ECM. Additionally, since cells can onlymigrate over living tissue, the epithelial cells excrete collagenasesand proteases such as matrix metalloproteinases (MMPs) to dissolvedamaged parts of the ECM in their migrational path. In the final phaseof epithelialization, contraction of the wound occurs as the fibroblastsdifferentiate into myofibroblasts to form the protective outer layer, orstratum corneum. Contraction can last for days or several weeks andcontinues even after the wound is completely reepithelialized.Contraction is the main cause of scarring associated with wound healing.

The remodeling stage generally begins when the levels of collagenproduction and degradation equalize. In other words, remodelinggenerally begins once a scar has formed and the tensile strength of thewound has begun to increase. The remodeling stage typically begins 7 to21 days post-injury and typically lasts for at least 3 weeks and canlast for months or years depending on factors such as wound size andre-injury.

In the remodeling stage, the wound matures to become stronger, e.g., tohave increased tensile strength. In general, weaker type III collagen,which is common at the wound site in the proliferation stage, isreplaced by stronger type I collagen. This replacement generallyinvolves reorganizing, crosslinking, and aligning the temporary collagenfibers. As remodeling progresses, the scar disappears.

FIG. 40 illustrates a depiction of wound healing over time. An upperportion of FIG. 40 shows a first wound healing graph 200 of tissuestrength (tensile force F) versus time (t). A lower portion of FIG. 40shows a second wound healing graph 202 of medicant dose amount versustime (t). The first and second graphs 200, 202 are plotted with a sharedhorizontal axis to facilitate comparison of data shown in the first andsecond graphs 200, 202. Time zero (t=0) in the first and second graphs200, 202 represents a time of injury, e.g., when a wound occurs. A firsttissue strength F1 in the first graph 200 thus represents the tissue'sstrength at the wound at the time of injury.

The first graph 200 includes a first curve 204 of tissue strength overtime during typical wound healing, and includes a second curve 206 oftissue strength over time during accelerated wound healing in accordancewith at least some methods, systems, and devices provided herein. Thesecond curve 206 of accelerated wound healing can be achieved using oneor more doses of medicants provided in the second graph 202, asdiscussed further below. Stages of wound healing (a hemostasis stage208, an inflammation stage 210, and a proliferation stage 212) are shownin FIG. 40 with reference to the second graph 202, and hence also to thesecond curve 206 of the first graph 200. The first curve 204 in thefirst graph 200 has a different timing of hemostasis, inflammation, andproliferation stages, as discussed below.

The time scale in FIG. 40 is an example only. As discussed above, thetiming of wound healing can vary, e.g., the stages of wound healing canbegin at different times for different wounds and/or for differentpatients. FIG. 40 demonstrates that for the same wound in the samepatient, the wound's typical healing, as illustrated by the first curve204, is improved when one or more medicants are dosed to the patient inaccordance with the second graph 202, as illustrated by the second curve206. In other words, regardless of the time scale of the horizontal axisof the first and second graphs 200, 202, the dosing of one or moremedicants may provide for faster wound healing than typical woundhealing and may provide a shorter period of minimum tissue tensilestrength than typical wound healing.

As demonstrated by the first curve 204, typical wound healing involvesthe tissue having the first tissue strength F1 at time zero anddecreasing in strength over time to a minimum tissue strength F4 thatbegins during day four (5>t>4) during an inflammation stage and persistsuntil sometime during day six (7>t>6) before tissue strength begins togradually improve back toward the first tissue strength F1. The firsttissue strength F1 can be re-achieved during typical wound healing, asshown by the first curve 204, at some point during or after aproliferation stage. The tissue's strength begins to decrease from thefirst tissue strength F1 in response to inflammation, e.g., in responseto entry into the inflammation stage, during day one (2>t>1) andcontinues decreasing toward and/or remains at its lowest level F4 untilinflammation of the tissue begins to subside, e.g., until theproliferation stage begins, during day six. The tissue is thusdecreasing in strength and is at its most vulnerable to succumb to anynumber of inflammation's adverse effects for a relatively long period oftime that starts during day one and lasts into day six.

As demonstrated by the second curve 206, accelerated wound healing inaccordance with at least some embodiments of the methods, systems, anddevices provided herein involves the tissue having the first tissuestrength F1 at time zero and decreasing in strength over time to aminimum tissue strength F3 that begins during day three (4>t>3) duringthe inflammation stage 210 and persists until sometime during day four(5>t>4) before tissue strength begins to gradually improve back towardthe first tissue strength F1. The minimum tissue strength F3 in theaccelerated wound healing is greater than the minimum tissue strength F4in the typical wound healing. The tissue experiencing the acceleratedwound healing thus never has strength as low as that during typicalwound healing. In other words, the accelerated wound healing allows forless tissue weakening than typical wound healing. The tissue's strengthbegins to decrease from the first tissue strength F1 in response toinflammation, e.g., in response to entry into the inflammation stage210, during day one (2>t>1) and continues decreasing toward and/orremains at its lowest level F3 until inflammation begins to improve,e.g., until the proliferation stage 212 begins, during day four. Thetissue is thus decreasing in strength and is at its most vulnerable tosuccumb to any number of inflammation's adverse effects sooner and for ashorter period of time than typical wound healing, i.e., starting duringday one and lasting into day four instead of starting during day one andlasting into day six. In other words, the accelerated wound healing canprovide for a shorter inflammation stage than typical wound healing. Thetissue's strength may not increase back to its pre-wound tissue strengthF1 after the inflammation stage 210 in the accelerated healing but canincrease to a level close thereto, as shown by the second curve 206reaching a new maximum tissue strength F2 during the proliferation stage212.

The second graph 202 illustrates an example of doses of medicants thatcan be administered to the patient to achieve the accelerated woundhealing indicated by the second curve 206. The doses of medicants caninclude a dose of medicant A configured to facilitate hemostasis in thehemostasis stage 208 as also shown in FIG. 41; doses of medicant B,medicant B₁, medicant C, and medicant C₁ configured to facilitateinflammation in the inflammation stage 210 as also shown in FIG. 42;doses of medicant D and medicant D₁ configured to inhibit MMPs during amacrophages phase 214 of the inflammation stage 210 (e.g., during a timewhen macrophages are present and active at the wound site in theinflammation stage 210) as also shown in FIG. 43; a dose of medicant Econfigured to prevent inflammation in the proliferation stage 212 duringa fibroblasts phase 216 of the proliferation stage 212 (e.g., during atime when fibroblasts are present and active at the wound site in theproliferation stage 212) as also shown in FIG. 44; and a dose ofmedicant F configured to facilitate tissue growth in the proliferationstage 212 during a fibroblasts phase 216 of the proliferation stage 212(e.g., during a time when fibroblasts are present and active at thewound site in the proliferation stage 212) as also shown in FIG. 44.Each of the medicants A, B, B₁, C, C₁, D, D₁, E, F is discussed furtherbelow.

In one example, at least one medicant can be administered to tissueduring each of the hemostasis, inflammation, and proliferation stages208, 210, 212 of the wound healing to overall improve the wound healingprocess with all of the medicants shown in the second graph 202 beingadministered, e.g., the medicant A in the hemostasis stage 208, themedicants B, B₁, C, D, D₁ in the inflammation stage 210, and themedicants E, F in the proliferation stage 212. In another example, atleast one medicant can be administered to tissue during each of thehemostasis, inflammation, and proliferation stages 208, 210, 212 of thewound healing to overall improve the wound healing process without allof the medicants shown in the second graph 202 being administered, e.g.,the medicant A in the hemostasis stage 208, at least one of themedicants B, B₁, C, C₁, D, D₁ in the inflammation stage 210 (and in afurther example, at least two of the medicants B, B₁, C, C₁, D, D₁), andone or both of the medicants E, F in the proliferation stage 212. Thesubset of the medicants A, B, B₁, C, C₁, D, D₁, E, F administered can bedetermined on a case-by-case basis based on any one or more factors suchas wound type, wound size, surgeon preference, available medicants at atime of surgery, patient medical history, etc. In yet another example,at least one medicant can be administered to tissue during only one ortwo of the hemostasis, inflammation, and proliferation stages 208, 210,212 to improve select stages of the wound healing process (with animprovement in one stage being able to improve subsequent stage(s) ofthe wound healing process, as discussed above) without all of themedicants shown in the second graph 202 being administered. Further, themedicants can be administered in the selected one or two stages as shownin the second graph 202 (e.g., the medicant A in the hemostasis stage,the medicants B, B₁, C, C₁, D, D₁ in the inflammation stage 210, themedicants E, F in the proliferation stage 212) or can be selectivelyadministered in the selected one or two stages (e.g., the medicant A inthe hemostasis stage 208, at least one of the medicants B, B₁, C, C₁, D,D₁ in the inflammation stage 210 (and in a further example, at least twoof the medicants B, B₁, C, C₁, D, D₁), one or both of the medicants E, Fin the proliferation stage 212). The one or two of the stages 208, 210,212 in which medicant doses are administered can be determined on acase-by-case basis based on any one or more factors such as wound type,wound size, surgeon preference, available medicants at a time ofsurgery, patient medical history, etc.

As discussed herein, an adjunct material including one or more medicantsreleasable therefrom can be delivered to tissue, e.g., using a surgicalstapler. The adjunct material's one or more medicants can include eachof the medicants A, B, B₁, C, C₁, D, D₁, E, F being administered,whether it be all of the medicants A, B, B₁, C, C₁, D, D₁, E, F or asubset thereof. The administered ones of the medicants A, B, B₁, C, C₁,D, D₁, E, F can thus be delivered to the patient concurrent with a timeof the injury (t=0). As discussed herein, the adjunct material'smedicants can be releasable therefrom in a variety of ways. The timingof the release can allow the medicants to be administered to tissue atthe appropriate time in the wound healing process, as also discussedherein. The medicants A, B, B₁, C, C₁, D, D₁, E, F (or the selectedsubset thereof) can thus be simultaneously delivered to the patient butcan be released to the patient's tissue at different times and over timeto achieve the desired effects.

The medicant A configured to facilitate hemostasis can have a variety ofconfigurations. In general, the medicant A can include a hemostaticagent configured to promote hemostasis. The administration of themedicant A may thus help stop bleeding and help shorten a length of thehemostasis stage 208 and, accordingly, help the inflammation stage 210begin sooner than in typical wound healing. Examples of the medicant Ainclude fibrin and thrombin. Also, examples of hemostatic agentsconfigured to promote hemostasis and delivery thereof are described inU.S. Pat. Pub. No. 2013/0149343 entitled “Hemostatic BioabsorbableDevice with Polyethylene Glycol Binder” filed Dec. 13, 2011, U.S. Pat.No. 8,383,147 entitled “Reinforced Absorbable Synthetic Matrix ForHemostatic Applications” filed Aug. 22, 2012, and U.S. Pat. No.8,329,211 entitled “Reinforced Absorbable Multi-Layered Fabric ForHemostatic Applications” filed May 17, 2010, which are herebyincorporated by reference in their entireties.

The medicant A can be administered in a variety of ways. In one example,the medicant A can be administered from a vessel. The vessel can includea bioabsorbable or dissolvable coating, e.g., a saccharide coating,etc., surrounding the medicant A. The coating can be configured tobioabsorb/dissolve relatively quickly so as to be administered to thewounded tissue within minutes of the injury, e.g., within minutes oft=0. The medicant A's hemostatic effects can thus begin prior to thestart of the inflammation stage 210. As shown in FIG. 40 and FIG. 41,the dose of the medicant A can decrease over time as the agentdissipates in the tissue/the patient's body.

The medicants B, B₁, C, C₁ configured to facilitate inflammation caneach have a variety of configurations. In general, the medicants B, B₁,C, C₁ can each include an inflammatory agent configured to promoteinflammation. The medicants B, B₁, C, C₁ may thus help speed up theinflammatory process and, accordingly, help shorten the inflammationstage 210 as compared to typical wound healing, help the proliferationstage 212 begin sooner than in typical wound healing, help the tissuereach its minimum strength F3 sooner than when the minimum strength F4is reached in typical wound healing, and help shorten a period of timeat which the tissue is at its minimum strength F3 as compared to typicalwound healing. Examples of the medicants B, B₁, C, C₁ includepro-inflammatory medicants. In some aspects, the medicants B, B₁, C, C₁can each include the same agent. In other aspects, the medicants B, B₁can each include the same agent, and the medicants C, C₁ can eachinclude the same agent as each other that is a different agent than themedicants B, B₁. In still other aspects, the medicants B, B₁, C, C₁ caneach include a different agent from one another.

The medicants B, B₁, C, C₁ can each be administered in a variety ofways. In one example, the medicant B can be administered as a vesselwith the medicant B₁ being a coating of the medicant B vessel, and themedicant C can be administered as another vessel with the medicant C₁being a coating of the medicant C vessel. The dosages of the vesselmedicants B, C can be greater than the dosages of the coating medicantsB₁, C₁, as shown in FIG. 40 and FIG. 42, as vessel coatings typicallyinclude less substance than the vessel that they surround.

In one example, the medicant B₁ can be configured to begin release priorto the medicant B, which can be configured to begin release prior to themedicant C₁, which can be configured to begin release prior to themedicant C. The inflammatory medicants B, B₁, C, C₁ can thus beconfigured to be stagger-released with each medicants' dose peaking at adifferent time (e.g., at a different point along the time t axis of thesecond graph 202). The different peak dosages of the inflammatorymedicants B, B₁, C, C₁ can allow the medicants B, B₁, C, C₁ to have acumulative inflammatory dose, shown as “BC” in FIG. 40 and FIG. 42,greater than any of their individual doses. In other words, the peakdosages of the individual medicants B, B₁, C, C₁ can be timed tocontribute to an overall inflammatory dose “BC” greater than can beachieved individually with their doses. The inflammatory dose “BC” cangenerally have the shape of a square wave, as also shown in FIG. 40 andFIG. 42.

The inflammatory medicants B, B₁, C, C₁ can be configured to each beginrelease prior to the release of the other medicants effective in theinflammation stage 210, the medicants D, D₁ configured to inhibit MMPs.In this way, the tissue at the wound site can be allowed to be inflamedand approach its minimum tensile strength F3 a short time before daythree (t=3), at which time the macrophage phase 214 of the inflammationstage 210 generally begins and during which the medicants D, D₁ can beadministered.

The medicants D, D₁ configured to inhibit MMPs can each have a varietyof configurations. In general, the medicants D, D₁ can each include anagent configured to inhibit MMP, e.g., an MMP inhibitor. The medicantsD, D₁ can thus help less MMP be released in the inflammation stage 210,thereby allowing less of the ECM to be destroyed in the inflammationstage 210. The tissue at the wound site may thus be less torn down whilestill allowing the inflammatory process and, accordingly, allow thetissue to have more strength than in the typical wound healing process,e.g., F3>F4. Examples of the medicants D, D₁ include tissue matrixdegradation inhibitors that inhibit the action of MMPs and otherproteases. In one example, the medicants D, D₁ each include the sameagent, but the medicants D, D₁ can differ from one another in at leastsome examples.

The medicants D, D₁ can each be administered in a variety of ways. Inone example, each of the medicants D, D₁ can be administered via vessel.Each of the two vessels can include a coating configured to facilitaterelease of the medicants D, D₁ at the appropriate time in the woundhealing process, e.g., at a time after release of the inflammatorymedicants B, B₁, C, C₁, such as sometime 4 to 7 days after the injury(4<t<7). Examples of the coating include a copolymer having 90%polyglycolide (also referred to as polyglycolic acid (PGA)) and 10%polylactide (also referred to as polyactic acid (PCA)), such as VicrylRapide.

In one example, the medicant D can be configured to begin release priorto the medicant D₁. The MMP-inhibiting medicants D, D₁ can thus beconfigured to be stagger-released with each medicants' dose peaking at adifferent time (e.g., at a different point along the time t axis of thesecond graph 202). The different peak dosages of the MMP-inhibitingmedicants D, D₁ can allow the medicants D, D₁ to have a cumulativeMMP-inhibiting dose, shown as “DD₁” in FIG. 40 and FIG. 43, greater thantheir individual doses. In other words, the peak dosages of theindividual medicants D, D₁ can be timed to contribute to an overallMMP-inhibiting dose “DD₁” greater than can be achieved individually withtheir doses.

The MMP-inhibiting medicants D, D₁ can be configured to each beginrelease prior to the release of the medicants E, F. In this way, thetissue at the wound site can be allowed to be inflamed and endure itsminimum tensile strength F3 before the proliferation stage 212 beginssometime during day four.

The medicant E configured to prevent inflammation can have a variety ofconfigurations. In general, the medicant E can include an agentconfigured to inhibit inflammation, e.g., an anti-inflammatory agent.The medicant E can thus be configured to help reduce inflammation at thewound site and, accordingly, help end the inflammation stage 210.Examples of the medicant E include diclofenac.

The medicant E can be administered in a variety of ways. In one example,the medicant E can be administered as a vessel. The vessel can include acoating configured to facilitate release of the medicant E at theappropriate time in the wound healing process, e.g., at a time afterrelease of the MMP-inhibiting medicants D, D₁, such as at least 4 daysafter the injury (4<t), e.g., sometime 7 to 10 days after the injury(7<t<10). Examples of the coating include a copolymer having 90% PGA and10% PCA and having a high molecular weight, e.g., a higher molecularweight than the coating used for the MMP-inhibiting medicants D, D₁ soas to be released thereafter.

The medicant F configured to facilitate tissue growth can have a varietyof configurations. In general, the medicant F can include an agentconfigured to promote tissue growth, e.g., a growth factor. The medicantF can thus be configured to help the tissue rebuild in the proliferationstage 212. Examples of the medicant F include TGF-β.

The medicant F can be administered in a variety of ways. In one example,the medicant F can be administered as a vessel. The vessel can include acoating configured to facilitate release of the medicant F at theappropriate time in the wound healing process, e.g., at a time afterrelease of the anti-inflammatory medicant E, such as at least 5 daysafter the injury (5<t), e.g., sometime 5 to 10 days after the injury(5<t<10). Examples of the coating include a copolymer having 65% PGA and35% PCA.

Implementations

Various exemplary adjuncts for surgical devices including agonists andantagonists are described herein. In general, an implantable adjunct canhave two or more medicants releasably disposed therein that are eachreleasable from the adjunct. At least one of the medicants can includean agonist configured to encourage a physiological response, and atleast one of the medicants can include an antagonist configured todiscourage the physiological response encouraged by the agonist. Inother words, the antagonist can be configured to counter the effect ofthe agonist. The physiological response can include an aspect related towound healing such that the aspect related to wound healing may be bothencouraged by and discouraged by the adjunct (e.g., encouraged by theagonist disposed in the adjunct and discouraged by the antagonistdisposed in the adjunct), which may help accelerate wound healingthrough control of the physiological response and, accordingly, helpreduce the adverse effects of wound healing.

For example, the physiological response can include inflammation suchthat the agonist is configured to encourage tissue inflammation and theantagonist is configured to discourage tissue inflammation. In this way,the agonist can encourage the inflammation that occurs in wound healing,e.g., the start of inflammation can be triggered by the agonist (e.g.,the agonist can trigger the start of wound healing's inflammation stage)and/or the agonist can accelerate inflammation during wound healing'sinflammation stage (e.g., cause the inflammation stage to proceed morequickly and hence be able to end sooner), and the antagonist candiscourage the inflammation that occurs in wound healing, e.g., theinflammation stage can be encouraged to end by the antagonist and/or thestart of wound healing's proliferation stage can be triggered by theantagonist. In other words, the agonist can be configured to encouragean acute inflammatory response, and the antagonist can be configured toprevent a chronic inflammatory response. By affecting inflammation incountering ways, the agonist and the antagonist may cooperate to limit alength of time that the wound experiences its lowest strength bylimiting a duration of the inflammation stage of wound healing, and/ormay cooperate to produce a higher minimum strength of the wound duringhealing. Thus, since a wounded tissue's strength is typically lowestduring the inflammation stage, as discussed above, the agonist and theantagonist may cooperate to limit an amount of time that the tissue isat its most vulnerable to succumb to any number of inflammation'sadverse effects. By way of example, with reference to FIG. 40, theagonist can include at least one of the medicant B, the medicant B₁, themedicant C, and the medicant C₁ each configured to facilitateinflammation in the inflammation stage 210, and the antagonist caninclude the medicant E configured to prevent inflammation in theproliferation stage 212 during the fibroblasts phase 216 thereof.

For another example, the physiological response can include a vascularresponse, e.g., vessel constriction and dilation. The agonist can beconfigured to encourage one of vessel constriction and dilation, and theantagonist can be configured to encourage the other of vesselconstriction and dilation so as to counter the effect of the agonist.

For yet another example, the physiological response can include bloodflow. The agonist can be configured to either encourage clotting (e.g.,slow bleeding) or to discourage clotting (e.g., accelerate bleeding),and the antagonist can be configured to affect blood flow opposite tothat of the agonist. The agonist can thus be configured to encourage thestoppage of acute bleeding, such as in the hemostasis stage of woundhealing, and the antagonist can be configured to help prevent excessiveclotting. Excessive clotting is typically not needed during the processof wound healing since a general goal of wound healing is to return thewounded tissue to a normal, pre-wounded condition.

For still another example, the physiological response can includeprobiotic effect or bacteria growth. The agonist can be configured toencourage proliferation of probiotics, e.g., to encourage bacterialgrowth, and the antagonist can be configured to discourage proliferationof probiotics, e.g., to discourage bacterial growth. Agonists andantagonists affecting probiotic effect or bacteria growth may beparticularly useful for wound healing in a gastrointestinal (GI)context, such as when an adjunct having an agonist and an antagonistdisposed therein is delivered to a colon, and in particular for helpingto minimize loss of GI tissue wall strength during the process of woundhealing.

The agonist and the antagonist can be configured to be non-homogenouslyreleased from the adjunct. To facilitate wound healing, the agonist canbe configured to begin releasing from the adjunct before the antagonistbegins releasing from the adjunct. In other words, each of the agonistand the antagonist can be configured to be released from the adjunctaccording to a different predetermined release profile, with thepredetermined release profile of the agonist allowing the agonist to bereleasable from the adjunct prior to the antagonist's release from theadjunct. In this way, the physiological response may be encouraged bythe agonist and then subsequently discouraged by the antagonist. Thephysiological response may thus be temporally controlled by the adjunctincluding the two or more medicants. Thus, wound healing may beaccelerated through temporal control of the physiological response thatincludes an aspect of wound healing.

Time release of the agonist and the antagonist from the adjunct can becontrolled in any of a variety of ways. The time release of the agonistand the antagonist can be independently controlled, such as by timing ofcoating disintegration, timing of polymer dissolution (e.g., timing ofthe dissolution of different polymers forming the adjunct, timing of thedissolution of the same polymer forming the adjunct where the polymer ispresent in different molecular weights, timing of the same polymerforming the adjunct where the polymer is present in different phasessuch as an amorphous phase and a crystalline phase that degrades slowerthan the amorphous phase, timing of the same polymer forming the adjunctwhere the polymer is present with different pretreatments (e.g.,irradiation such as gamma sterilization, exposure to light, exposure toa liquid that initiates hydrolysis that is stopped before packaging ofthe adjunct such as by oven drying, exposure to air, etc.) altering howthe polymer degrades), or via application of pressure thereto, asdiscussed above. The agonist and the antagonist can thus each beconfigured to begin release from the adjunct at a predetermined time,with the predetermined times not being affected by one another.

Alternatively, the time release of the antagonist can be dependent onthe time release of the agonist. In other words, the timing of theagonist's release from the adjunct can influence the timing of theantagonist's release from the adjunct. The antagonist's release can thusbe self-regulated. For example, the agonist's release can be configuredto start encouraging the physiological response, e.g., begin encouragingtissue inflammation, and the antagonist can be configured to be releasedproportionately to a magnitude of the physiologic response encouraged bythe agonist, e.g., by a magnitude of the tissue inflammation. Theantagonist may thus be able to more effectively counter the effects ofthe agonist by being configured to begin releasing from the adjunctbefore the physiological response becomes too intense, before thephysiological response lasts beyond a maximum amount of tolerable timepost-wound occurrence, and/or after the agonist has had sufficient timeto effectively encourage the physiological response. Medicantsconfigured to regulate the release of another medicant are furtherdescribed in U.S. patent application Ser. Ser. No. 14/840,716 entitled“Adjunct Material To Provide Controlled Drug Release” filed on Aug. 31,2015, which is hereby incorporated by reference in its entirety.

Each of the agonist and the antagonist releasably retained in theadjunct can include one or more different medicants, with each of theindividual medicants being present at a single intensity orconcentration or being present in two or more different intensities orconcentrations.

As discussed above, release of the agonist can begin eithersubstantially immediately upon delivery of the adjunct to tissue, or theagonist's release can be delayed until a predetermined time after theadjunct's delivery to tissue. The antagonist, being configured to beginrelease from the adjunct after the start of the agonist's release fromthe adjunct, can have its release from the adjunct delayed until apredetermined time, which can be a predetermined time after theadjunct's delivery to tissue or after the start of the agonist'srelease. The antagonist can be configured to start releasing from theadjunct before or after all of the agonist has been released from theadjunct. In other words, release of the agonist and the antagonist canoverlap in time, or the releases can be non-overlapping in time. By wayof example, with reference to FIG. 40, the agonist as including at leastone of the medicants B, B₁, C, C₁ each configured to facilitateinflammation in the inflammation stage 210 and the antagonist includingthe medicant E configured to prevent inflammation in the proliferationstage 212 are released from an adjunct at non-overlapping times duringwound healing.

The two or more medicants releasably retained in the adjunct can includeonly the agonist and the antagonist, e.g., include only one or moreagonists and one or more antagonists. The adjunct and the medicantsdisposed therein may thus be targeted to affect the physiologicalresponse, which may allow the adjunct to be selected by a surgeon orother medical professional for delivery to tissue when the physiologicalresponse is of particular concern for a particular patient and/or for aparticular wound type, and/or which may allow the adjunct to bedelivered to a location on tissue where the physiological response maymost need controlling (e.g., where the tissue is most at risk ofinflammation, etc.) and one or more other adjuncts having one or moreother types of medicants releasably retained therein to be delivered toanother location on the tissue to target one or more other aspects ofwound healing. By way of example, with reference to FIG. 40, the agonistcan include at least one of the medicant B, the medicant B₁, themedicant C, and the medicant C₁, and the antagonist can include themedicant E such that the only medicants retained by the adjunct includethe medicant E and one or more of the medicants B, B₁, C, C₁.

Alternatively, the two or more medicants releasably retained in theadjunct can include the agonist, the antagonist, and at least one othertype of medicant, e.g., include one or more agonists, one or moreantagonists, and one or more medicants configured to encourage aresponse other than the physiological response targeted by the agonistand the antagonist. The adjunct and the medicants disposed therein maythus be configured to affect the physiological response and to affectone or more other aspects of wound healing, which may allow the adjunctto more comprehensively improve the process of wound healing than whenthe adjunct only includes the agonist and the antagonist and/or mayallow the adjunct to improve more stages in the process of wound healingthan when the adjunct only includes the agonist and the antagonist. Forexample, the agonist (which can include one or more medicants) can beconfigured to encourage inflammation in the inflammation stage of woundhealing, the antagonist (which can include one or more medicants) can beconfigured to discourage inflammation in the proliferation stage ofwound healing, and the one or more medicants configured to encourage aresponse other than the physiological response can include at least oneof a medicant (which can include one or more medicants) configured tofacilitate hemostasis, a medicant (which can include one or moremedicants) configured to inhibit MMPs during the macrophages phase ofthe inflammation stage, and a medicant (which can include one or moremedicants) configured to facilitate tissue growth in the proliferationstage of wound healing. By way of example, with reference to FIG. 40,the agonist can include at least one of the medicant B, the medicant B₁,the medicant C, and the medicant C₁, the antagonist can include themedicant E, and the other medicant can include any one or more of themedicants A, D, D₁, F.

For another example, with reference to FIG. 45, the agonist can includea first medicant 1300, and the antagonist can include a second medicant1302. The time scale in FIG. 45 is an example only. As shown, theagonist 1300 can be configured to begin release from an adjunct at atime zero (e.g., a time of wound healing), peak in dosage at a start ofDay 1, and cease release from the adjunct at a start of Day 2, and theantagonist 1302 can be configured to begin release from the adjunct at astart of Day 2, peak in dosage at a start of Day 3, and cease releasefrom the adjunct at a start of Day 4. The antagonist 1302 can thus beconfigured to start releasing from the adjunct when the agonist 1300stops being released from the adjunct. The agonist 1300 can thus beallowed to induce its full effects on the targeted physiologicalresponse before the antagonist 1302 begins to cancel the effects of theagonist 1300 by discouraging the physiological response.

As discussed above, the agonist 1300 and the antagonist 1302 can be theonly medicants releasably retained in the adjunct, or at least oneadditional medicant can be releasably retained in the adjunct. Forexample, as shown in FIG. 45, the adjunct can have a third medicant 1304releasable therefrom. The third medicant 1304 can have a variety ofdifferent release timings from the adjunct. In this illustratedimplementation, the third medicant 1304 is configured to begin releasefrom the adjunct at a start of Day 1, peak in dosage at a start of Day2, and cease release from the adjunct at a start of Day 3. The thirdmedicant 1304 can thus be configured to be released over time to overlapwith the release of both the agonist 1300 and the antagonist 1302.

In at least some implementations, instead of being a medicant other thanan agonist or antagonist, the third medicant 1304 can be an agonist oran antagonist. In this way, the third medicant 1304 as an agonist cancooperate with the first agonist 1300 to encourage the samephysiological response, or the third medicant 1304 as an antagonist cancooperate with the second antagonist 1302 to discourage the samephysiological response.

The agonist 1300, the antagonist 1302, and (if present) the thirdmedicant 1304 can each be released from the adjunct as a single dose, asshown by the solid lines for the agonist 1300, the antagonist 1302, andthe third medicant 1304 in FIG. 45. Alternatively, any one or more ofthe agonist 1300, the antagonist 1302, and third medicant 1304 can bereleased as cumulative doses. Each additional cumulative dose releasedat substantially the same time as its associated single dose is shown inFIG. 45 by a dotted line, e.g., two doses of the agonist 1300 shown asdotted line 1300A, three doses of the agonist 1300 shown as dotted line1300B, four doses of the agonist 1300 shown as dotted line 1300C, twodoses of the antagonist 1302 shown as dotted line 1302A, three doses ofthe antagonist 1302 shown as dotted line 1302B, four doses of theantagonist 1302 shown as dotted line 1302C, two doses of the thirdmedicant 1304 shown as dotted line 1304A, three doses of the thirdmedicant 1304 shown as dotted line 1304B, and four doses of the thirdmedicant 1304 shown as dotted line 1304C. A person skilled in the artwill appreciate that medicants/doses may not be released at preciselythe same time due to any one or more factors, such as accuracy of timemeasurement devices and/or small temporal differences in when medicantsreleased from the adjunct directly contact tissue, but nevertheless beconsidered to be effectively released at substantially the same time.

For another example, with reference to FIG. 46, the agonist can includea first medicant including three doses 1306A, 1306B, 1306C thereof, andthe antagonist can include a second medicant including a single dose1308 thereof. The time scale in FIG. 46 is an example only. The threeagonist doses 1306A, 1306B, 1306C can provide a cumulative dose 1310, asshown in FIG. 47. In other implementations, as discussed herein, theagonist and the antagonist can be delivered using other numbers ofdoses. As shown in FIG. 46, the first agonist dose 1306A beginsreleasing from the adjunct at time zero of wound creation and peaks indosage at a start of Day 1, the second agonist dose 1306B beginsreleasing from the adjunct at a start of Day 1 and peaks in dosage at astart of Day 2, the third agonist dose 1306C begins releasing from theadjunct at a start of Day 2 and peaks in dosage at a start of Day 3, andthe antagonist dose 1308 begins releasing from the adjunct at a start ofDay 5 and peaks in dosage at a start of Day 6. Additionally, as shown,the first agonist dose 1306A stops releasing from the adjunct at a startof Day 2, the second agonist dose 1306B stops releasing from the adjunctat a start of Day 3, the third agonist dose 1306C stops releasing fromthe adjunct at a start of Day 4, and the antagonist dose 1308 stopsreleasing from the adjunct at a start of Day 7.

FIG. 48 illustrates one example of a vessel 1316 including the first andsecond medicants of FIG. 46. The vessel 1316 can be configured to bereleasably retained in an adjunct (not shown) such that the first andsecond medicants can release therefrom via the vessel 1316. Similar tothe vessel 174 of FIG. 31, the vessel 1316 includes a plurality ofdistinct concentric layers. As shown, an outermost layer includes afirst dose 1318A of the agonist, a layer inner of the outermost layerincludes a second dose 1318B of the agonist, a layer inner of the seconddose layer includes a third dose 1318C of the agonist, and an innermostlayer includes a dose 1320 of the antagonist. As discussed herein, theadjunct can include a plurality of the vessels 1316. Together, theplurality of vessels 1316 can release the first and second medicantstherefrom to achieve the doses 1306A, 1306B, 1306C of the agonist andthe single dose of the antagonist 1308. Thus, the first dose 1318A ofeach of the vessels 1316 form the first agonist dose 1306A, the seconddose 1318B of each of the vessels 1316 form the second agonist dose1306B, the third dose 1318C of each of the vessels 1316 form the thirdagonist dose 1306C, and the dose 1320 of each of the vessels 1316 formthe antagonist dose 1308.

Referring again to FIG. 46, the agonist including the three doses 1306A,1306B, 1306C and the antagonist including the single dose 1308 can bethe only medicants releasably retained in the adjunct, or at least oneadditional medicant can be releasably retained in the adjunct. Forexample, as shown, the adjunct can have a third medicant including asingle dose 1312, and can have a fourth medicant including two doses1314A, 1314B. The third and fourth medicants can each have anothernumber of doses than those shown in this illustrated implementation. Thesecond and fourth medicants are each shown in FIG. 46 as single doses1308, 1312, but one or both can include multiple doses to form acumulative dose. Similarly, the first and third medicants are each shownin FIG. 46 as including multiple doses that form a cumulative dose, butone or both can include single doses. In an exemplary implementation,the third medicant can be configured to facilitate hemostasis in thehemostasis stage of wound healing, the first medicant (agonist) can beconfigured to facilitate inflammation in the inflammation stage of woundhealing, the fourth medicant can be configured to inhibit MMP in theinflammation stage of wound healing, and the second medicant(antagonist) can be configured to prevent inflammation in theproliferation stage of wound healing.

As mentioned above, an adjunct including an agonist and an antagonistreleasably retained therein can have a variety of configurations. Oneexample of such an adjunct is the adjunct 171 of FIG. 30 that includesfirst and second vessels 170, 172 that include first and secondmedicants D1, D2 encapsulated within the coatings A3, B3. The firstmedicant 170 can include an agonist, and the second medicant 172 caninclude an antagonist. The agonist can thus be configured to start beingreleased from the adjunct before the antagonist since the degradationrate of the first vessel's outer coating A3 is faster than the secondvessel's outer coating B3. The time release of the first and secondmedicants D1, D2 can therefore be controlled by the coatings A3, B3.

In at least some implementations, an adjunct including an agonist and anantagonist releasably retained therein can be a fiber-based lattice. Theadjunct as a fiber-based lattice can have a variety of configurations,as discussed herein. In general, separate fibers forming the fiber-basedlattice can have discrete absorption profiles such that a first subsetof the fibers breaks down in the healing cascade and thereby releases anagonist and then, subsequent to the start of the breakdown of the firstsubset of fibers, a second subset of the fibers breaks down in thehealing cascade and thereby releases an antagonist. The first and secondsubsets of fibers can each include fibers having a certain conformationthat is changeable, such as by the action of water and/or other agentsthat the adjunct is subjected to at the treatment site, e.g., the fiberscan each be configured to unwind or fray. The conformation change canallow for medicant release from the fibers. For example, the firstsubset of fibers may begin to break down to release an inflammatoryagent such as prostaglandin F2-alpha (PGF 2α), and the second subset offibers may begin to break down at a point in time after the first subsetof fibers begin to break down to release an anti-inflammatory agent suchas a non-steroidal anti-inflammatory agent (NSAID) or an acetic acidderivative.

The first and second subsets of fibers can form the entire lattice ofthe adjunct such that the adjunct's only medicants include the agonistand the antagonist. Alternatively, the adjunct can include additionalfibers that form the lattice with the first and second subsets offibers. The additional fibers can be base fibers that are configured tonot break down in the healing cascade, are configured to providestructural support to the adjunct, and are not configured to facilitaterelease of a medicant from the adjunct such that the adjunct's onlymedicants include the agonist and the antagonist. Alternatively, theadditional fibers can be configured to break down in the healing cascadeand release one or more medicants therefrom such that the adjunct'smedicants include the agonist, the antagonist, and at least oneadditional type of medicant.

FIG. 49 and FIG. 50 illustrate one implementation of a fiber 1322configured to release a medicant 1324 therefrom. The medicant 1324 can,as shown, be a coating of the fiber 1322 that has a width 1324 w. Thecoating is only shown as being along a partial longitudinal length ofthe fiber 1322, but the coating can extend along a partial longitudinallength of the fiber 1322 or along the entire longitudinal length of thefiber 1322. The coating, and hence the medicant 1324, can be configuredto absorb, dissolve, or otherwise disintegrate as discussed herein forcoatings so as to release the medicant 1324 from an adjunct includingthe fiber 1322 as part of its fiber-based lattice. The adjunct can beformed from a plurality of the fibers 1322, with the fibers 1322 beingthe only fibers that form the fiber-based lattice or with the fibers1322 being one or at least two types of fibers forming the fiber-basedlattice.

The coating (e.g., the medicant 1324) is shown as being directly on anexterior surface of the fiber 1322. In other implementations, there canbe at least one intermediate layer between the coating and the exteriorsurface of the fiber 1322, such as at least one coating of anothermedicant. Additionally, although the coating itself in this illustratedimplementation includes the medicant 1324, in other implementations, thefiber 1322 can have the medicant 1324 trapped thereon by a coatingdisposed over the medicant 1324 that is configured to disintegrate toallow release of the medicant 1324 from the fiber 1322.

FIG. 51 and FIG. 52 illustrate another implementation of a fiber 1326configured to release a medicant 1328 therefrom. The medicant 1328 can,as shown, be a coating of the fiber 1326 that has a width 1328 w. Thecoating is only shown as being along a partial longitudinal length ofthe fiber 1326, but the coating can extend along a partial longitudinallength of the fiber 1326 or along the entire longitudinal length of thefiber 1326. The coating, and hence the medicant 1328, can be configuredto absorb, dissolve, or otherwise disintegrate as discussed herein forcoatings so as to release the medicant 1328 from an adjunct includingthe fiber 1326 as part of its fiber-based lattice. Similar to thatdiscussed above regarding the fiber 1322 and the medicant 1324, thecoating (e.g., the medicant 1328) can be directly on an exterior surfaceof the fiber 1326, as shown, or there can be at least one intermediatelayer between the coating and the exterior surface of the fiber 1326.Also similar to that discussed above regarding the fiber 1322 and themedicant 1324, the coating can include the medicant 1328, as shown, orthe coating can trap the medicant 1328 on the fiber 1326.

The adjunct can be formed from a plurality of the fibers 1326, with thefibers 1326 being the only fibers that form the fiber-based lattice orwith the fibers 1326 being one or at least two types of fibers formingthe fiber-based lattice. For example, the fiber-based lattice caninclude a plurality of the fibers 1322 and a plurality of the fibers1326. The coating on the fibers 1322 has the width 1324 w that is lessthan the coating on the fibers 1324 w. Thus, in the case of the fiber1322 having the medicant 1324 trapped thereon by the coating disposedthereover and the fiber 1326 having the medicant 1328 trapped thereon bythe coating disposed thereover, the coatings can have a substantiallysame rate of degradation. A person skilled in the art will appreciatethat each of the coatings may not have precisely the same rate ofdegradation due to any one or more factors, such as accuracy of timemeasurement devices and/or small temporal differences in whendegradation begins, but nevertheless be considered to be the same. Themedicant 1324, which can include an agonist, can thus be released beforethe medicant 1328, which can include an antagonist, due to the width1324 w of the coating on the fiber 1322 being less than the width 1328 wof the coating on the fiber 1326.

FIG. 53 illustrates additional implementations of first, second, andthird types of fibers 1330, 1332, 1334 configured to release a medicanttherefrom. The first, second, and third types of fibers 1330, 1332, 1334each include fibers having a certain conformation that is changeable byeach including twisted fibers configured to change in conformation byunwinding or fraying.

The first type of fibers 1330 includes a coating 1336 thereon that isconfigured to absorb, dissolve, or otherwise disintegrate as discussedherein for coatings. The coating 1336 can itself include a medicant, orthe coating 1336 can overlay a medicant on an outer surface of the fiberthat is releasable from the fiber due to the coating's disintegration.

The second type of fibers 1332 has a plurality of pellets 1338 attachedthereto. As discussed herein, the pellets 1338 can each have adissolvable coating such that, as the coating is disintegrated, themedicant can be distributed as a bolus dose or as a time release dosage.The pellets 1338 can be more densely packed on the fibers 1332 closer toa center of an adjunct 1340 including the first, second, and thirdfibers 1330, 1332, 1334, which may allow more of the medicant to bedelivered the more the fibers interact with fluid or other matter thatdissolves the coating. Additionally or alternatively, the medicant ofthe pellets 1338 can be on a progressive time release pattern in whichmedicant adjacent the adjunct's outer edge 1342 releases faster from thepellets 1338 than from pellets 1338 more toward the center of theadjunct 1340. In at least some implementations, the medicant of thepellets 1338 closer to an outer edge 1342 of the adjunct 1340 caninclude an agonist, and the medicant of the pellets 1338 farther fromthe outer edge 1342 and closer to a center of the adjunct 1340 caninclude an antagonist. Thus, as the fibers 1332 unwind or fray from theouter edge 1342 toward the adjunct's center, the agonist is firstreleased from the adjunct 1340 and the antagonist is subsequentlyreleased from the adjunct 1340.

The third type of fibers 1334 includes a plurality of smaller-diameterfibers 1344 braided together to form the fiber. A medicant can be“hidden” within the braid and be released in response to the braidunwinding or fraying. In at least some implementations, the medicant“hidden” in the braid closer to the outer edge 1342 can include anagonist, and the medicant “hidden” in the braid farther from the outeredge 1342 and closer to the adjunct's center can include an antagonist.Thus, as the fibers 1334 unwind or fray from the outer edge 1342 towardthe adjunct's center, the agonist is first released from the adjunct1340 and the antagonist is subsequently released from the adjunct 1340.

As shown, the adjunct 1340 can include a fourth type of fibers 1346,which can have a certain conformation that is not changeable, e.g., thefourth types of fibers 1346 can be configured to not unwind or fray. Thenon-changeable fourth type of fibers 1346 form a base of the adjunct1340 so as to provide structural stability to the adjunct 1340 and,hence, to provide structural stability to a wound to which the adjunct1340 is delivered.

Only a portion of the adjunct 1340 is shown at the outer edge 1342thereof. An adjunct can include any combination of the types of fibers1330, 1332, 1334, 1346 shown in FIG. 53.

In at least some implementations of an adjunct having an agonist and anantagonist disposed therein, the agonist can include first and secondmedicants each configured to encourage a physiological response, and theantagonist can include a third medicant configured to discourage thephysiological response. The first medicant can be configured to beginreleasing from the adjunct first among the first, second, and thirdmedicants. The first medicant can be configured to start thephysiological response, e.g., to trigger a start of the inflammationstage of wound healing.

The second medicant can be configured to begin releasing from theadjunct at a time after the first medicant has started releasing fromthe adjunct. The time can be either before the first medicant is fullyreleased from the adjunct or after the first medicant has been fullyreleased from the adjunct. The second medicant can be configured toreinforce and accelerate the physiological response. The start of therelease of the second medicant from the adjunct can be based on thephysiological response, such as a based on an intensity of thephysiological response as indicated by pH. For example, the secondmedicant can be configured to begin releasing from the adjunct once thepH at the wound to which the adjunct has been delivered reaches acertain value that triggers breakdown of a coating or a polymer.

The third medicant can be configured to counter the effect of thephysiological response. The start of the release of the third medicantfrom the adjunct can be based on the physiological response, such as abased on an intensity of the physiological response. In the case of thephysiological response including inflammation, the third medicant canthus help discourage inflammation in proportion to the inflammation thatactually occurred.

In an exemplary implementation, the adjunct having one or more agonistsand one or more antagonists releasably disposed therein can beconfigured to be applied to tissue by a surgical stapler in conjunctionwith staples.

A person skilled in the art will appreciate that the present inventionhas application in conventional minimally-invasive and open surgicalinstrumentation as well application in robotic-assisted surgery.

The devices disclosed herein can be designed to be disposed of after asingle use, or they can be designed to be used multiple times. In eithercase, however, the device can be reconditioned for reuse after at leastone use. Reconditioning can include any combination of the steps ofdisassembly of the device, followed by cleaning or replacement ofparticular pieces and subsequent reassembly. In particular, the devicecan be disassembled, and any number of the particular pieces or parts ofthe device can be selectively replaced or removed in any combination.Upon cleaning and/or replacement of particular parts, the device can bereassembled for subsequent use either at a reconditioning facility, orby a surgical team immediately prior to a surgical procedure. Thoseskilled in the art will appreciate that reconditioning of a device canutilize a variety of techniques for disassembly, cleaning/replacement,and reassembly. Use of such techniques, and the resulting reconditioneddevice, are all within the scope of the present application.

One skilled in the art will appreciate further features and advantagesof the invention based on the above-described embodiments. Accordingly,the invention is not to be limited by what has been particularly shownand described, except as indicated by the appended claims. Allpublications and references cited herein are expressly incorporatedherein by reference in their entirety.

What is claimed:
 1. A staple cartridge assembly for use with a surgicalstapler, comprising: a cartridge body having a plurality of staplecavities, each staple cavity having a surgical staple disposed therein;a biocompatible adjunct material releasably retained on the cartridgebody and configured to be delivered to tissue by deployment of thestaples in the cartridge body; a first medicant disposed within andreleasable from the adjunct material according to a predeterminedrelease profile, the first medicant includes an agonist configured toencourage a physiological response; a second medicant disposed withinand releasable from the adjunct material according to a predeterminedrelease profile, the second medicant includes an antagonist configuredto discourage the physiological response encouraged by the agonist; anda plurality of capsules disposed within the adjunct material, each ofthe capsules including a plurality of bioabsorbable or dissolvablelayers, the first medicant being included in a layer outer of a layerthat includes the second medicant, each bioabsorbable or dissolvablelayer including a first polymer, each bioabsorbable or dissolvable layerbeing a polymer layer including the first polymer in a differentpolymeric phase such that the predetermined release profile of the firstmedicant is different than the predetermined release profile of thesecond medicant.
 2. The assembly of claim 1, wherein according to thepredetermined release profile of the first medicant the agonist isreleased from the adjunct material before the antagonist is releasedfrom the adjunct material according to the predetermined release profileof the second medicant.
 3. The assembly of claim 1, wherein according tothe predetermined release profile of the first medicant the agonist issubstantially fully released from the adjunct material before theantagonist begins release from the adjunct material according to thepredetermined release profile of the second medicant.
 4. The assembly ofclaim 1, wherein the physiological response includes inflammation suchthat the agonist is configured to encourage tissue inflammation and theantagonist is configured to discourage tissue inflammation.
 5. Theassembly of claim 1, wherein the layer including the first medicant isdisposed directly adjacent to the layer including the second medicant.6. The assembly of claim 1, wherein a layer including a third medicantis disposed between the layer including the first medicant and the layerincluding the second medicant.
 7. The assembly of claim 1, wherein theadjunct material including a plurality of fibers, the first medicantbeing coated on a first subset of the fibers and the second medicantbeing coated on a second subset of the fibers.
 8. An end effector for asurgical instrument, comprising: a first jaw having a cartridge bodyremovably attached thereto, the cartridge body having on a tissue-facingsurface thereof a plurality of staple cavities configured to seatstaples therein; a second jaw having an anvil with a plurality of stapleforming cavities formed on a tissue-facing surface thereof, wherein atleast one of the first and second jaws is movable relative to the other;a biocompatible adjunct material releasably retained on at least one ofthe tissue-facing surfaces of the cartridge body and the anvil, andconfigured to be delivered to tissue by deployment of the staples in thecartridge body; a first medicant disposed within and releasable from theadjunct material according to a predetermined release profile, the firstmedicant includes an agonist configured to encourage a physiologicalresponse; a second medicant disposed within and releasable from theadjunct material according to a predetermined release profile, thesecond medicant includes an antagonist configured to discourage thephysiological response encouraged by the agonist; and a plurality ofcapsules disposed within the adjunct material and each including aplurality of bioabsorbable or dissolvable layers, the first medicantbeing included in a layer outer of a layer that includes the secondmedicant, the predetermined release profile of the second medicant beingdetermined by a severity of the physiological response encouraged by thefirst medicant.
 9. The end effector of claim 8, wherein according to thepredetermined release profile of the first medicant the agonist isreleased from the adjunct material before the antagonist is releasedfrom the adjunct material according to the predetermined release profileof the second medicant.
 10. The end effector of claim 8, whereinaccording to the predetermined release profile of the first medicant theagonist is substantially fully released from the adjunct material beforethe antagonist begins release from the adjunct material according to thepredetermined release profile of the second medicant.
 11. The endeffector of claim 8, wherein the physiological response includesinflammation such that the agonist is configured to encourage tissueinflammation and the antagonist is configured to discourage tissueinflammation.
 12. The end effector of claim 8, wherein the layerincluding the first medicant is disposed directly adjacent to the layerincluding the second medicant.
 13. The end effector of claim 8, whereina layer including a third medicant is disposed between the layerincluding the first medicant and the layer including the secondmedicant.
 14. The end effector of claim 8, wherein the adjunct materialincluding a plurality of fibers, the first medicant being coated on afirst subset of the fibers and the second medicant being coated on asecond subset of the fibers.